Pharmaceutical composition and method for treating hypogonadism

ABSTRACT

A pharmaceutical composition useful for treating hypogonadism is disclosed. The composition comprises an androgenic or anabolic steroid, a C1-C4 alcohol, a penetration enhancer such as isopropyl myristate, and water. Also disclosed is a method for treating hypogonadism utilizing the composition.

FIELD OF THE INVENTION

[0001] The present invention is directed to a pharmaceutical compositioncomprising testosterone in a gel formulation, and to methods of usingthe same.

BACKGROUND OF THE INVENTION A. Testosterone Metabolism in Men

[0002] Testosterone is the major circulating androgen in men. More than95% of the 6-7 mg of testosterone produced per day is secreted by theapproximately 500 million Leydig cells in the testes. Two hormonesproduced by the pituitary gland, luteinizing hormone (“LH”) and folliclestimulating hormone (“FSH”), are required for the development andmaintenance of testicular function.

[0003] The most important hormone for the regulation of Leydig cellnumber and function is LH. In eugonadal men, LH secretion from thepituitary is inhibited through a negative-feedback pathway by increasedconcentrations of testosterone through the inhibition of the release ofgonadotropin-releasing hormone (“GRH”) by the hypothalamus. FSH promotesspermatogenesis and is essential for the normal maturation of sperm. FSHsecretion from the pituitary normally is inhibited through anegative-feedback pathway by increased testosterone concentrations.

[0004] Testosterone is responsible primarily for the development andmaintenance of secondary sex characteristics in men. In the body,circulating testosterone is metabolized to various 17-keto steroidsthrough two different pathways. Testosterone can be metabolized todihydrotestosterone (“DHT”) by the enzyme 5α-reductase. There are twoforms of 5α-reductase in the body: one form is found predominately inthe liver and non-genital skin while another form is found in theurogenital tract of the male and the genital skin of both sexes.Testosterone can also be metabolized to estradiol (“E₂”) by an aromataseenzyme complex found in the liver, fat, and the testes.

[0005] Testosterone circulates in the blood 98% bound to protein. Inmen, approximately 40% of the binding is to the high-affinity sexhormone binding globulin (“SHBG”). The remaining 60% is bound weakly toalbumin. Thus, a number of measurements for testosterone are availablefrom clinical laboratories. The term “free” testosterone as used hereinrefers to the fraction of testosterone in the blood that is not bound toprotein. The term “total testosterone” or “testosterone” as used hereinmeans the free testosterone plus protein-bound testosterone. The term“bioavailable testosterone” as used herein refers to the non-SHBG boundtestosterone and includes that weakly bound to albumin.

[0006] The conversion of testosterone to DHT is important in manyrespects. For example, DHT binds with greater affinity to SHBG than doestestosterone. In addition, in many tissues, the activity of testosteronedepends on the reduction to DHT, which binds to cytosol receptorproteins. The steroid-receptor complex is then transported to thenucleus where it initiates transcription and cellular changes related toandrogen action. DHT is also thought to lower prostate volume andinhibit tumor development in the prostate. Thus, given the importance ofDHT and testosterone in normal body functioning, researchers frequentlyassess and report androgen concentrations in patients as total androgen(“DHT +T”) or as a ratio of DHT to testosterone (“DHT/T ratio”).

[0007] The following table from the UCLA-Harbor Medical Centersummarizes the hormone concentrations in normal adult men range: TABLE 1Hormone Levels in Normal Men Hormone Normal Range Testosterone   298 to1043 ng/dL Free testosterone  3.5 to 17.9 ng/dL DHT   31 to 193 ng/dLDHT/T Ratio 0.052 to 0.33 DHT + T   372 to 1349 ng/dL SHBG  10.8 to 46.6nmol/L FSH  1.0 to 6.9 mlU/mL LH  1.0 to 8.1 mlU/mL E₂  17.1 to 46.1pg/mL

[0008] There is considerable variation in the half-life of testosteronereported in the literature, ranging from 10 to 100 minutes. Researchersdo agree, however, that circulating testosterone has a diurnal variationin normal young men. Maximum levels occur at approximately 6:00 to 8:00a.m. with levels declining throughout the day. Characteristic profileshave a maximum testosterone level of 720 ng/dL and a minimum level of430 ng/dL. The physiological significance of this diurnal cycle, if any,however, is not clear.

B. Hypogonadal Men and Current Treatments for Hypogonadism

[0009] Male hypogonadism results from a variety of patho-physiologicalconditions in which testosterone concentration is diminished below thenormal range. The hypogonadic condition is sometimes linked with anumber of physiological changes, such as diminished interest in sex,impotence, reduced lean body mass, decreased bone density, lowered mood,and energy levels.

[0010] Researchers generally classify hypogonadism into one of threetypes. Primary hypogonadism includes the testicular failure due tocongenital or acquired anorchia, XYY Syndrome, XX males, Noonan'sSyndrome, gonadal dysgenesis, Leydig cell tumors, maldescended testes,varicocele, Sertoli-Cell-Only Syndrome, cryptorchidism, bilateraltorsion, vanishing testis syndrome, orchiectomy, Klinefelter's Syndrome,chemotherapy, toxic damage from alcohol or heavy metals, and generaldisease (renal failure, liver cirrhosis, diabetes, myotoniadystrophica). Patients with primary hypogonadism show an intact feedbackmechanism in that the low serum testosterone concentrations areassociated with high FSH and LH concentrations. However, because oftesticular or other failures, the high LH concentrations are noteffective at stimulating testosterone production.

[0011] Secondary hypogonadism involves an idiopathic gonadotropin orLH-releasing hormone deficiency. This type of hypogonadism includesKallman's Syndrome, Prader-Labhart-Willi's Syndrome,Laurence-Moon-Biedl's Syndrome, pituitary insufficiency/adenomas,Pasqualini's Syndrome, hemochromatosis, hyperprolactinemia, orpituitary-hypothalamic injury from tumors, trauma, radiation, orobesity. Because patients with secondary hypogonadism do not demonstratean intact feedback pathway, the lower testosterone concentrations arenot associated with increased LH or FSH levels. Thus, these men have lowtestosterone serum levels but have gonadotropins in the normal to lowrange.

[0012] Third, hypogonadism may be age-related. Men experience a slow butcontinuous decline in average serum testosterone after approximately age20 to 30 years. Researchers estimate that the decline is about 1-2% peryear. Cross-sectional studies in men have found that the meantestosterone value at age 80 years is approximately 75% of that at age30 years. Because the serum concentration of SHBG increases as men age,the fall in bioavailable and free testosterone is even greater than thefall in total testosterone. Researchers have estimated thatapproximately 50% of healthy men between the ages of 50 and 70 havelevels of bioavailable testosterone that are below the lower normallimit. Moreover, as men age, the circadian rhythm of testosteroneconcentration is often muted, dampened, or completely lost. The majorproblem with aging appears to be within the hypothalamic-pituitary unit.For example, researchers have found that with aging, LH levels do notincrease despite the low testosterone levels. Regardless of the cause,these untreated testosterone deficiencies in older men may lead to avariety of physiological changes, including sexual dysfunction,decreased libido, loss of muscle mass, decreased bone density, depressedmood, and decreased cognitive function. The net result is geriatrichypogonadism, or what is commonly referred to as “male menopause.”

[0013] Today, hypogonadism is the most common hormone deficiency in men,affecting 5 in every 1,000 men. At present, it is estimated that onlyfive percent of the estimated four to five million American men of allages with hypogonadism currently receive testosterone replacementtherapy. Thus, for years, researchers have investigated methods ofdelivering testosterone to men. These methods include intramuscularinjections (43%), oral replacement (24%), pellet implants (23%), andtransdermal patches (10%). A summary of these methods is shown in Table2. TABLE 2 Mode of Application and Dosage of Various TestosteronePreparations Preparation Route Of Application Full Substitution Dose InClinical Use Testosterone enanthate Intramuscular injection 200-25.0 gevery 2-3 weeks Testosterone cypionate Intramuscular injection  200 mgevery 2 weeks Testosterone undecanoate Oral 2-4 capsules at 40 mg perday Transdermal testosterone patch Scrotal skin 1 membrane per dayTransdermal testosterone patch Non-scrotal skin 1 or 2 systems per dayTestosterone implants Implantation under the 3-6 implants of 200 mgevery 6 abdominal skin months Under Development Testosteronecyclodextrin Sublingual 2.5-5.0 mg twice daily Testosterone undecanoateIntramuscular injection 1000 mg every 8-10 weeks Testosterone buciclateIntramuscular injection 1000 mg every 12-16 weeks Testosteronemicrospheres Intramuscular injection  315 mg for 11 weeks Obsolete17α-Methyltestosterone Oral  25-5.0 g per day Fluoxymesterone Sublingual  10-25 mg per day Oral   10-20 mg per day

[0014] As discussed below, all of the testosterone replacement methodscurrently employed suffer from one or more drawbacks, such asundesirable pharmacokinetic profiles or skin irritation. Thus, althoughthe need for an effective testosterone replacement methodology hasexisted for decades, an alternative replacement therapy that overcomesthese problems has never been developed. The present invention isdirected to a 1% testosterone hydroalcoholic gel that overcomes theproblems associated with current testosterone replacement methods.

1. Subdermal Pellet Implants

[0015] Subdermal implants have been used as a method of testosteronereplacement since the 1940s. The implant is produced by meltingcrystalline testosterone into a cylindrical form. Today, pellet implantsare manufactured to contain either 100 mg (length 6 mm, surface area 117mm²) or 200 mg of testosterone (length 12 mm, surface area 202 mm²).Patients receive dosages ranging from 100 to 1,200 mg, depending on theindividual's requirements. The implants are inserted subcutaneouslyeither by using a trocar and cannula or by open surgery into an areawhere there is relatively little movement. Frequently, the implant isplaced in the lower abdominal wall or the buttock. Insertion is madeunder local anesthesia, and the wound is closed with an adhesivedressing or a fine suture.

[0016] Implants have several major drawbacks. First, implants require asurgical procedure which many hypogonadal men simply do not wish toendure. Second, implant therapy includes a risk of extrusion (8.5%),bleeding (2.3%), or infection (0.6%). Scarring is also a risk. Perhapsmost important, the pharmacokinetic profile of testosterone pelletimplant therapy fails to provide men with a suitable consistenttestosterone level. In general, subdermal testosterone implants producesupra-physiologically high serum testosterone levels which slowlydecline so that before the next injection subnormally low levels oftestosterone are reached. For example, in one recent pharmacokineticstudy, hypogonadal patients who received six implants (1,200 mgtestosterone) showed an initial short-lived burst release oftestosterone within the first two days after application. A stableplateau was then maintained over then next two months (day 2: 1,015ng/dL; day 63: 990 ng/dL). Thereafter, the testosterone levels declinedto baseline by day 300. DHT serum concentrations also rose significantlyabove the baseline, peaking at about 63 days after implementation andgreatly exceeding the upper limit of the normal range. From day 21 today 189, the DHT/T ratio was significantly increased. Thepharmacokinetic profiles for testosterone, DHT, and DHT/T in this studyare shown in FIG. 1. See Jockenhovel et al., Pharmacokinetics andPharmacodynamics of Subcutaneous Testosterone Implants in HypogonadalMen, 45 CLINICAL ENDOCRINOLOGY 61-71 (1996). Other studies involvingimplants have reported similar undesirable pharmacokinetic profiles.

2. Injection of Testosterone Esters

[0017] Since the 1950s, researchers have experimented with theintermuscular depot injection of testosterone esters (such as enanthate,cypionate) to increase testosterone serum levels in hypogonadal men.More recent studies have involved injection of testosterone buciclate ortestosterone undecanoate in an oil-based vehicle. Other researchers haveinjected testosterone microcapsule formulations.

[0018] Testosterone ester injection treatments suffer from manyproblems. Patients receiving injection therapy often complain that thedelivery mechanism is painful and causes local skin reactions. Inaddition, testosterone microcapsule treatment requires two simultaneousintramuscular injections of a relatively large volume, which may bedifficult to administer due to the high viscosity of the solution andthe tendency to block the needle. Other men generally find testosteroneinjection therapy inconvenient because injection usually requires thepatient to visit his physician every two to three weeks.

[0019] Equally important, injection-based testosterone replacementtreatments still create an undesirable pharmacokinetic profile. Theprofile generally shows a supra-physiologic testosterone concentrationduring the first 24 to 48 hours followed by a gradual fall—often tosub-physiologic levels—over then next few weeks. These high serumtestosterone levels, paralleled by increases in E₂, are also consideredthe reason for acne and gynecomastia occurring in some patients, and forpolycythaemia, occasionally encountered especially in older patientsusing injectable testosterone esters. In the case of testosteronebuciclate injections, the treatment barely provides normal androgenserum levels and the maximal increase of serum testosterone overbaseline does not exceed 172 ng/dL (6 nmol/dL ) on average. Becauselibido, potency, mood, and energy are thought to fluctuate with theserum testosterone level, testosterone injections have largely beenunsuccessful in influencing these variables. Thus, testosteroneinjection remains an undesirable testosterone replacement treatmentmethod.

3. Oral/Sublingual/Buccal Preparations of Androgens

[0020] In the 1970s, researchers began using with oral, sublingual, orbuccal preparations of androgens (such as fluoxymesterone,17α-methyl-testosterone or testosterone undecanoate) as a means fortestosterone replacement. More recently, researchers have experimentedwith the sublingual administration oftestosterone-hydroxypropyl-beta-cyclodextrin inclusion complexes.Predictably, both fluoxymesterone and methyl testosterone are17-alkylated and thus associated with liver toxicity. Because thesesubstances must first pass through the liver, they also produce anunfavorable effect on serum lipid profile, increasing LDL and decreasingHDL, and carbohydrate metabolism. While testosterone undecanoate haspreferential absorption through the intestinal lymphatics, it has notbeen approved in the United States.

[0021] The pharmacokinetic profiles for oral, sublingual, and buccaldelivery mechanisms are also undesirable because patients are subjectedto super-physiologic testosterone levels followed by a quick return tothe baseline. For example, one recent testing of a buccal preparationshowed that patients obtained a peak serum hormone levels within 30minutes after administration, with a mean serum testosteroneconcentration of 2,688+/−147 ng/dL and a return to baseline in 4 to 6hours. See Dobs et al., Pharmacokinetic Characteristics, Efficacy andSafety of Buccal Testosterone in Hypogonadal Males: A Pilot Study, 83 J.CLINICAL ENDOCRINOLOGY & METABOLISM 33-39 (1998). To date, the abilitythese testosterone delivery mechanisms to alter physiological parameters(such muscle mass, muscle strength, bone resorption, urinary calciumexcretion, or bone formation) is inconclusive. Likewise, researchershave postulated that super-physiologic testosterone levels may not haveany extra beneficial impact on mood parameters such anger, nervousness,and irritability.

4. Testosterone Transdermal Patches

[0022] The most recent testosterone delivery systems have involvedtransdermal patches. Currently, there are three patches used in themarket: TESTODERM®, TESTODERM® TTS, and ANDRODERM®.

a. TESTODERM®

[0023] TESTODERM® (Alza Pharmaceuticals, Mountain View, Calif.) was thefirst testosterone-containing patch developed. The TESTODERM® patch iscurrently available in two sizes (40 or 60 cm²). The patch contains 10or 15 mg of testosterone and delivers 4.0 mg or 6.0 mg of testosteroneper day. TESTODERM® is placed on shaved scrotal skin, aided byapplication of heat for a few seconds from a hair dryer.

[0024]FIG. 2 shows a typical pharmacokinetic profile testosteroneprofile for both the 40 cm² and 60 cm² patch. Studies have also shownthat after two to four weeks of continuous daily use, the average plasmaconcentration of DHT and DHT/T increased four to five times abovenormal. The high serum DHT levels are presumably caused by the increasedmetabolism of 5α-reductase in the scrotal skin.

[0025] Several problems are associated with the TESTODERM® patch. Notsurprisingly, many men simply do not like the unpleasant experience ofdry-shaving the scrotal hair for optimal contact. In addition, patientsmay not be able to wear close-fitting underwear when undergoingtreatment. Men frequently experience dislodgment of the patch, usuallywith exercise or hot weather. In many instances, men experience itchingand/or swelling in the scrotal area. Finally, in a number of patients,there is an inability to achieve adequate serum hormone levels.

b. TESTODERM® TTS

[0026] The most recently developed non-scrotal patch is TESTODERM® TTS(Alza Pharmaceuticals, Mountain View, Calif.). It is an occlusive patchapplied once daily to the arm, back, or upper buttocks. The system iscomprised of a flexible backing of transparent polyester/ethylene-vinylacetate copolymer film, a drug reservoir of testosterone, and anethylene-vinyl acetate copolymer membrane coated with a layer ofpolyisobutylene adhesive formulation. A protective liner ofsilicone-coated polyester covers the adhesive surface.

[0027] Upon application, serum testosterone concentrations rise to amaximum at two to four hours and return toward baseline within two hoursafter system removal. Many men, however, are unable to obtain and/orsustain testosterone levels within the normal range. The pharmacokineticparameters for testosterone concentrations are shown as follows: TABLE 3TESTODERM ®TTS Testosterone Parameters Parameters Day 1 Day 5 C_(max)(ng/dL) 482 ± 149 473 ± 148 T_(max) (h) 3.9 3.0 C_(min) (ng/dL) 164 ±104 189 ± 86  T_(min) (h) 0 0

[0028] The typical 24-hour steady state testosterone concentrationachieved with TESTODERM® TTS patch is shown in FIG. 3.

[0029] Because of TESTODERM® patch is applied to the scrotal skin whilethe TESTODERM TTS® patch is applied to non-scrotal skin, the two patchesprovide different steady-state concentrations of the two majortestosterone metabolites, DTH and E₂,: TABLE 4 Hormone Levels UsingTESTODERM ® and TESTODERM ® TTS Hormone Placebo TESTODERM ® TESTODERM ®TTS DHT (ng/dL) 11 134 38 E₂ (pg/ml) 3.8 10 21.4

[0030] Likewise, in contrast to the scrotal patch, TESTODERM TTS®treatment creates a DHT/T ratio that is not different from that of aplacebo treatment. Both systems, however, suffer from similar problems.In clinical studies, TESTODERM® TTS is associated with transient itchingin 12% of patients, erythema in 3% of patients, and puritus in 2% ofpatients. Moreover, in one 14-day study, 42% of patients reported threeor more detachments, 33% of which occurred during exercise.

c. ANDRODERM®

[0031] ANDRODERM® (Watson Laboratories, Inc., Corona, Calif.) is atestosterone-containing patch applied to non-scrotal skin. The circularpatch has a total surface area of 37 cm.² The patch consists of a liquidreservoir containing 12.2 mg of testosterone and a permeation-enhancedvehicle containing ethanol, water, monoglycerides, fatty acid esters,and gelling agents. The suggested dose of two patches, applied eachnight in a rotating manner on the back, abdomen, upper arm, or thigh,delivers 4.1 to 6.8 mg of testosterone.

[0032] The steady state pharmacokinetic profile of a clinical studyinvolving ANDRODERM® is shown in FIG. 4. In general, upon repeatedapplication of the ANDRODERM® patch, serum testosterone levels increasegradually for eight hours after each application and then remain at thisplateau level for about another eight hours before declining.

[0033] In clinical trials, ANDRODERM® is associated with skin irritationin about a third of the patients, and 10% to 15% of subjects have beenreported to discontinue the treatment because of chronic skinirritation. Preapplication of corticosteroid cream at the site ofapplication of ANDRODERM® has been reported to decrease the incidenceand severity of the skin irritation. A recent study, however, found thatthe incidence of skin reactions sufficiently noxious enough to interrupttherapy was as high as 52%. See Parker et al., Experience withTransdermal Testosterone Replacement in Hypogonadal Men, 50 CLINICALENDOCRINOLOGY (OXF) 57-62 (1999). The study reported:

[0034] Two-thirds of respondents found the Andropatch unsatisfactory.Patches were variously described as noisy, visually indiscrete,embarrassing, unpleasant to apply and remove, and generally to besocially unacceptable. They fell off in swimming pools and showers,attracted ribald comments from sporting partners, and left bald redmarks over trunk and limbs. Dogs, wives, and children were distracted bynoise of the patches with body movements. Those with poor mobility ormanual dexterity (and several were over 70 years of age) found itdifficult to remove packaging an apply patches dorsally.

d. Transdermal Patch Summary

[0035] In sum, the transdermal patch generally offers an improvedpharmacokinetic profile compared to other currently used testosteronedelivery mechanisms. However, as discussed above, the clinical andsurvey data shows that all of these patches suffer from significantdrawbacks, such as buritus, burn-like blisters, and erythema. Moreover,one recent study has concluded that the adverse effects associated withtransdermal patch systems are “substantially higher” than reported inclinical trials. See Parker, supra. Thus, the transdermal patch stillremains an inadequate testosterone replacement therapy alternative formost men.

5. DHT Gels

[0036] Researchers have recently begun investigating the application ofDHT to the skin in a transdermal gel. However, the pharmacokinetics of aDHT-gel is markedly different from that of a testosterone gel.Application of DTH-gel results in decreased serum testosterone, E₂, LH,and FSH levels. Thus, DHT gels are not effective at increasingtestosterone levels in hypogonadal men.

[0037] Accordingly, there is a definite need for a testosteroneformulation that safely and effectively provides an optimal andpredictable pharmacokinetic profile.

SUMMARY OF THE INVENTION

[0038] The foregoing problems are solved and a technical advance isachieved with the present invention. The present invention generallycomprises a testosterone gel. Daily transdermal application of the gelin hypogonadal men results in a unique pharmacokinetic steady-stateprofile for testosterone. Long-term treatment further results inincreased bone mineral density, enhanced libido, enhanced erectilefrequency and satisfaction, increased positive mood, increased musclestrength, and improved body composition without significant skinirritation. The present invention is also directed to a unique method ofadministering the testosterone gel employing a packet having apolyethylene liner compatible with the components of the gel.

BRIEF DESCRIPTION OF THE DRAWINGS

[0039]FIG. 1 is a graph of testosterone concentrations, DHTconcentrations, and the DHT/T ratio for patients receiving a subdermaltestosterone pellet implant over a period of 300 days afterimplantation.

[0040]FIG. 2 is a 24-hour testosterone pharmacokinetic profile forpatients receiving the 40 cm² or 60 cm² TESTODERM® patch.

[0041]FIG. 3 is a 24-hour testosterone pharmacokinetic profile forpatients receiving the TESTODERM® TTS patch.

[0042]FIG. 4 is a 24-hour testosterone pharmacokinetic profile forpatients receiving the ANDRODERM® patch.

[0043]FIG. 5(a) is a graph showing the 24-hour testosteronepharmacokinetic profile for hypogonadal men prior to receiving 5.0 g/dayof AndroGel®, 10.0 g/day of AndroGel®, or the testosterone patch (byinitial treatment group).

[0044]FIG. 5(b) is a graph showing the 24-hour testosteronepharmacokinetic profile for hypogonadal men on the first day oftreatment with either 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®,or the testosterone patch (by initial treatment group).

[0045]FIG. 5(c) is a graph showing the 24-hour testosteronepharmacokinetic profile for hypogonadal men on day 30 of treatment witheither 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, or thetestosterone patch (by initial treatment group).

[0046]FIG. 5(d) is a graph showing the 24-hour testosteronepharmacokinetic profile for hypogonadal men on day 90 of treatment witheither 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, or thetestosterone patch (by initial treatment group).

[0047]FIG. 5(e) is a graph showing the 24-hour testosteronepharmacokinetic profile for hypogonadal men on day 180 of treatment witheither 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, or thetestosterone patch (by final treatment group).

[0048]FIG. 5(f) is a graph showing the 24-hour testosteronepharmacokinetic profile for hypogonadal men on day 0, 1, 30, 90, and 180of treatment with 5.0 g/day of AndroGel®.

[0049]FIG. 5(g) is a graph showing the 24-hour testosteronepharmacokinetic profile for hypogonadal men on day 0, 1, 30, 90, and 180of treatment with 10.0 g/day of AndroGel®.

[0050]FIG. 5(h) is a graph showing the 24-hour testosteronepharmacokinetic profile for hypogonadal men on day 0, 1, 30, 90, and 180of treatment with the testosterone patch.

[0051]FIG. 6(a) is a graph showing the 24-hour free testosteronepharmacokinetic profile for hypogonadal men on day 1 of treatment witheither 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, or thetestosterone patch (by initial treatment group).

[0052]FIG. 6(b) is a graph showing the 24-hour free testosteronepharmnacokinetic profile for hypogonadal men on day 30 of treatment witheither 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, or thetestosterone patch (by initial treatment group).

[0053]FIG. 6(c) is a graph showing the 24-hour free testosteronepharmacokinetic profile for hypogonadal men on day 90 of treatment witheither 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, or thetestosterone patch (by initial treatment group).

[0054]FIG. 6(d) is a graph showing the 24-hour free testosteronepharmacokinetic profile for hypogonadal men on day 180 of treatment witheither 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, or thetestosterone patch (by final treatment group).

[0055]FIG. 6(e) is a graph showing the 24-hour free testosteronepharmacokinetic profile for hypogonadal men on day 0, 1, 30, 90, and 180of treatment with 5.0 g/day of AndroGel®.

[0056]FIG. 6(f) is a graph showing the 24-hour free testosteronepharmacokinetic profile for hypogonadal men on day 0, 1, 30, 90, and 180of treatment with 10.0 g/day of AndroGel®.

[0057]FIG. 6(g) is a graph showing the 24-hour free testosteronepharmacokinetic profile for hypogonadal men on day 0, 1, 30, 90, and 180of treatment with the testosterone patch.

[0058]FIG. 7 is a graph showing the DHT concentrations on days 0 through180 for hypogonadal men receiving either 5.0 g/day of AndroGel®, 10.0g/day of AndroGel®, or the testosterone patch (by initial treatmentgroup).

[0059]FIG. 8 is a graph showing the DHT/T ratio on days 0 through 180for hypogonadal men receiving either 5.0 g/day of AndroGel®, 10.0 g/dayof AndroGel®, or the testosterone patch (by initial treatment group).

[0060]FIG. 9 is a graph showing the total androgen concentrations (DHT+T) on days 0 through 180 for hypogonadal men receiving either 5.0 g/dayof AndroGel®, 10.0 g/day of AndroGel®, or the testosterone patch (byinitial treatment group).

[0061]FIG. 10 is a graph showing the E₂ concentrations on days 0 through180 for hypogonadal men receiving either 5.0 g/day of AndroGel®, 10.0g/day of AndroGel®, or the testosterone patch (by initial treatmentgroup).

[0062]FIG. 11 is a graph showing the SHBG concentrations on days 0through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel®,10.0 g/day of AndroGel®, or the testosterone patch (by initial treatmentgroup).

[0063]FIG. 12(a) is a graph showing the FSH concentrations on days 0through 180 for men having primary hypogonadism and receiving either 5.0g/day of AndroGel®, 10.0 g/day of AndroGel®, or the testosterone patch(by initial treatment group).

[0064]FIG. 12(b) is a graph showing the FSH concentrations on days 0through 180 for men having secondary hypogonadism and receiving either5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, or the testosteronepatch (by initial treatment group).

[0065]FIG. 12(c) is a graph showing the FSH concentrations on days 0through 180 for men having age-associated hypogonadism and receivingeither 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, or thetestosterone patch (by initial treatment group).

[0066]FIG. 12(d) is a graph showing the FSH concentrations on days 0through 180 for men having hypogonadism of an unknown origin andreceiving either 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, or thetestosterone patch (by initial treatment group).

[0067]FIG. 13(a) is a graph showing the LH concentrations on days 0through 180 for men having primary hypogonadism and receiving either 5.0g/day of AndroGel®, 10.0 g/day of AndroGel®, or the testosterone patch(by initial treatment group).

[0068]FIG. 13(b) is a graph showing the LH concentrations on days 0through 180 for men having secondary hypogonadism and receiving either5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, or the testosteronepatch (by initial treatment group).

[0069]FIG. 13(c) is a graph showing the LH concentrations on days 0through 180 for men having age-associated hypogonadism and receivingeither 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, or thetestosterone patch (by initial treatment group).

[0070]FIG. 13(d) is a graph showing the LH concentrations on days 0through 180 for men having hypogonadism of an unknown origin andreceiving either 5.0 g/day of AndroGel®, 10.0 g/day of AndroGel®, or thetestosterone patch (by initial treatment group).

[0071]FIG. 14(a) is a bar graph showing the change in hip BMD forhypogonadal men after 180 days of treatment with 5.0 g/day of AndroGel®,7.5 g/day of AndroGel®, 10.0 g/day of AndroGel®, or the testosteronepatch.

[0072]FIG. 14(b) is a bar graph showing the change in spine BMD forhypogonadal men after 180 days of treatment with 5.0 g/day of AndroGel®,7.5 g/day of AndroGel®, 10.0 g/day of AndroGel®, or the testosteronepatch

[0073]FIG. 15 is a graph showing PTH concentrations on days 0 through180 for hypogonadal men receiving either 5.0 g/day of AndroGel®, 10.0g/day of AndroGel®, or the testosterone patch (by initial treatmentgroup).

[0074]FIG. 16 is a graph showing SALP concentrations on days 0 through180 for hypogonadal men receiving either 5.0 g/day of AndroGel®, 10.0g/day of AndroGel®, or the testosterone patch (by initial treatmentgroup).

[0075]FIG. 17 is a graph showing the osteocalcin concentrations on days0 through 180 for hypogonadal men receiving either 5.0 g/day ofAndroGel®, 10.0 g/day of AndroGel®, or the testosterone patch (byinitial treatment group).

[0076]FIG. 18 is a graph showing the type I procollagen concentrationson days 0 through 180 for hypogonadal men receiving either 5.0 g/day ofAndroGel®, 10.0 g/day of AndroGel®, or the testosterone patch (byinitial treatment group).

[0077]FIG. 19 is a graph showing the N-telopeptide/Cr ratio on days 0through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel®,10.0 g/day of AndroGel®, or the testosterone patch (by initial treatmentgroup).

[0078]FIG. 20 is a graph showing the Ca/Cr ratio on days 0 through 180for hypogonadal men receiving either 5.0 g/day of AndroGel®, 10.0 g/dayof AndroGel®, or the testosterone patch (by initial treatment group).

[0079]FIG. 21(a) is a graph showing sexual motivation scores on days 0through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel®,7.5 g/day 10.0 g/day of AndroGel®, or the testosterone patch.

[0080]FIG. 21(b) is a graph showing overall sexual desire scores on days0 through 180 for hypogonadal men receiving either 5.0 g/day ofAndroGel®, 7.5 g/day 10.0 g/day of AndroGel®, or the testosterone patch.

[0081]FIG. 21(c) is a graph showing sexual enjoyment (with a partner)scores on days 0 through 180 for hypogonadal men receiving either 5.0g/day of AndroGel®, 7.5 g/day 10.0 g/day of AndroGel®, or thetestosterone patch.

[0082]FIG. 22(a) is a graph showing sexual performance scores on days 0through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel®,7.5 g/day 10.0 g/day of AndroGel®, or the testosterone patch.

[0083]FIG. 22(b) is a graph showing erection satisfaction performancescores on days 0 through 180 for hypogonadal men receiving either 5.0g/day of AndroGel®, 7.5 g/day 10.0 g/day of AndroGel®, or thetestosterone patch.

[0084]FIG. 22(c) is a graph showing percent erection scores on days 0through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel®,7.5 g/day 10.0 g/day of AndroGel®, or the testosterone patch.

[0085]FIG. 23(a) is a graph showing positive mood scores on days 0through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel®,7.5 g/day 10.0 g/day of AndroGel®, or the testosterone patch.

[0086]FIG. 23(b) is a graph showing negative mood scores on days 0through 180 for hypogonadal men receiving either 5.0 g/day of AndroGel®,7.5 g/day 10.0 g/day of AndroGel®, or the testosterone patch.

[0087]FIG. 24(a) is a bar graph showing the change in leg strength ondays 90 and 180 for hypogonadal men receiving either 5.0 g/day ofAndroGel®, 7.5 g/day 10.0 g/day of AndroGel®, or the testosterone patch.

[0088]FIG. 24(b) is a bar graph showing the change in arm strength ondays 90 and 180 for hypogonadal men receiving either 5.0 g/day ofAndroGel®, 7.5 g/day 10.0 g/day of AndroGel®, or the testosterone patch.

[0089]FIG. 25(a) is a bar graph showing the change in total body mass ondays 90 and 180 for hypogonadal men receiving either 5.0 g/day ofAndroGel®, 7.5 g/day 10.0 g/day of AndroGel®, or the testosterone patch.

[0090]FIG. 25(b) is a bar graph showing the change in lean body mass ondays 90 and 180 for hypogonadal men receiving either 5.0 g/day ofAndroGel®, 7.5 g/day 10.0 g/day of AndroGel®, or the testosterone patch.

[0091]FIG. 25(c) is a bar graph showing the change in fat mass on days90 and 180 for hypogonadal men receiving either 5.0 g/day of AndroGel®,7.5 g/day 10.0 g/day of AndroGel®, or the testosterone patch.

[0092]FIG. 25(d) is a bar graph showing the change in percent body faton days 90 and 180 for hypogonadal men receiving either 5.0 g/day ofAndroGel®, 7.5 g/day 10.0 g/day of AndroGel®, or the testosterone patch.

DETAILED DESCRIPTION OF THE INVENTION

[0093] While the present invention may be embodied in many differentforms, several specific embodiments are discussed herein with theunderstanding that the present disclosure is to be considered only as anexemplification of the principles of the invention, and it is notintended to limit the invention to the embodiments illustrated.

[0094] The present invention is directed to a pharmaceutical compositionfor percutaneous administration comprising at least one activepharmaceutical ingredient (e.g., testosterone) in a hydroalcoholic gel.In a broad aspect of the invention, the active ingredients employed inthe composition may include anabolic steroids such as androisoxazole,bolasterone, clostebol, ethylestrenol, formyldienolone,4-hydroxy-19-nortestosterone, methenolone, methyltrienolone, nandrolone,oxymesterone, quinbolone, stenbolone, trenbolone; androgenic steroidssuch as boldenone, fluoxymesterone, mestanolone, mesterolone,methandrostenolone, 17-methyltestosterone, 17 α-methyl-testosterone3-cyclopentyl enol ether, norethandrolone, normethandrone, oxandrolone,oxymetholone, prasterone, stanlolone, stanozolol, dihydrotestosterone,testosterone; and progestogens such as anagestone, chlormadinoneacetate, delmadinone acetate, demegestone, dimethisterone,dihydrogesterone, ethinylestrenol, ethisterone, ethynodiol, ethynodioldiacetate, flurogestone acetate, gestodene, gestonorone caproate,haloprogesterone, 17-hydroxy- 16-methylene-progesterone, 17β-hydroxyprogesterone, 17 α-hydroxyprogesterone caproate, medrogestone,medroxyprogesterone, megestrol acetate, melengestrol, norethindrone,norethindrone acetate, norethynodrel, norgesterone, norgestimate,norgestrel, norgestrienone, 19-norprogesterone, norvinisterone,pentagestrone, progesterone, promegestone, quingestrone, andtrengestone; and all enantiomers, isomers and derivatives of thesecompounds. (Based upon the list provided in The Merck Index, Merck & Co.Rahway, N.J. (1998)).

[0095] In addition to the active ingredient, the gel comprises one ormore lower alcohols, such as ethanol or isopropanol; a penetrationenhancing agent; a thickener; and water. Additionally, the presentinvention may optionally include salts, emollients, stabilizers,antimicrobials, fragrances, and propellants.

[0096] A “penetration enhancer” is an agent known to accelerate thedelivery of the drug through the skin. These agents also have beenreferred to as accelerants, adjuvants, and sorption promoters, and arecollectively referred to herein as “enhancers.” This class of agentsincludes those with diverse mechanisms of action including those whichhave the function of improving the solubility and diffusibility of thedrug, and those which improve percutaneous absorption by changing theability of the stratum corneum to retain moisture, softening the skin,improving the skin's permeability, acting as penetration assistants orhair-follicle openers or changing the state of the skin such as theboundary layer.

[0097] The penetration enhancer of the present invention is a functionalderivative of a fatty acid, which includes isosteric modifications offatty acids or non-acidic derivatives of the carboxylic functional groupof a fatty acid or isosteric modifications thereof. In one embodiment,the functional derivative of a fatty acid is an unsaturated alkanoicacid in which the —COOH group is substituted with a functionalderivative thereof, such as alcohols, polyols, amides and substitutedderivatives thereof. The term “fatty acid” means a fatty acid that hasfour (4) to twenty-four (24) carbon atoms. Non-limiting examples ofpenetration enhancers include C8-C22 fatty acids such as isostearicacid, octanoic acid, and oleic acid; C8-C22 fatty alcohols such as oleylalcohol and lauryl alcohol; lower alkyl esters of C8-C22 fatty acidssuch as ethyl oleate, isopropyl myristate, butyl stearate, and methyllaurate; di(lower)alkyl esters of C6-C8 diacids such as diisopropyladipate; monoglycerides of C8-C22 fatty acids such as glycerylmonolaurate; tetrahydrofurfuryl alcohol polyethylene glycol ether;polyethylene glycol, propylene glycol; 2-(2-ethoxyethoxy)ethanol;diethylene glycol monomethyl ether; alkylaryl ethers of polyethyleneoxide; polyethylene oxide monomethyl ethers; polyethylene oxide dimethylethers; dimethyl sulfoxide; glycerol; ethyl acetate; acetoacetic ester;N-alkylpyrrolidone; and terpenes.

[0098] The thickeners used herein may include anionic polymers such aspolyacrylic acid (CARBOPOL®by B. F. Goodrich Specialty Polymers andChemicals Division of Cleveland, Ohio), carboxymethylcellulose and thelike. Additional thickeners, enhancers and adjuvants may generally befound in United States Pharmacopeia/National Formulary (2000);Remington's The Science and Practice of Pharmacy, Meade Publishing Co.

[0099] The amount of drug to be incorporated in the composition variesdepending on the particular drug, the desired therapeutic effect, andthe time span for which the gel is to provide a therapeutic effect. Thecomposition is used in a “pharmacologically effective amount.” Thismeans that the concentration of the drug is such that in the compositionit results in a therapeutic level of drug delivered over the term thatthe gel is to be used. Such delivery is dependent on a number ofvariables including the drug, the form of drug, the time period forwhich the individual dosage unit is to be used, the flux rate of thedrug from the gel, surface area of application site, etc. The amount ofdrug necessary can be experimentally determined based on the flux rateof the drug through the gel, and through the skin when used with andwithout enhancers.

[0100] One such testosterone gel has only recently been made availablein the United States under the trademark AndroGel® by UnimedPharmaceuticals, Inc., Deerfield, Ill., one of the assignees of thisapplication. In one embodiment, the gel is comprised of the followingsubstances in approximate amounts: TABLE 5 Composition of AndroGel ®AMOUNT (w/w) PER 100 g OF SUBSTANCE GEL Testosterone  1.0 g Carbopol 9800.90 g Isopropyl myristate 0.50 g 0.1 N NaOH 4.72 g Ethanol (95% w/w) 72.5 g* Purified water (qsf)  100 g

[0101] One skilled in the art will appreciate that the constituents ofthis formulation may be varied in amounts yet continue to be within thespirit and scope of the present invention. For example, the compositionmay contain about 0.1 to about 10.0 g of testosterone, about 0.1 toabout 5.0 g Carbopol, about 0.1 to about 5.0 g isopropyl myristate, andabout 30.0 to about 98.0 g ethanol.

[0102] A therapeutically effective amount of the gel is rubbed onto agiven area of skin by the user. The combination of the lipophilictestosterone with the hydroalcoholic gel helps drive the testosterone into the outer layers of the skin where it is absorbed and then slowlyreleased into the blood stream. As demonstrated by the data presentedherein, the administration of the gel of the present invention has asustained effect.

[0103] Toxicity and therapeutic efficacy of the active ingredients canbe determined by standard pharmaceutical procedures, e.g., fordetermining LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀(the dose therapeutically effective in 50% of the population). The doseratio between toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio LD₅₀/ED₅₀. Compounds which exhibitlarge therapeutic induces are preferred. While compounds that exhibittoxic side effects may be used, care should be taken to design adelivery system that targets such compounds to the site of affectedtissue in order to minimize potential damage to uninfected cells and,thereby, reduce side effects.

[0104] The term “treatment” as used herein refers to any treatment of ahuman condition or disease and includes: (1) preventing the disease orcondition from occurring in a subject which may be predisposed to thedisease but has not yet been diagnosed as having it, (2) inhibiting thedisease or condition, i.e., arresting its development, (3) relieving thedisease or condition, i.e., causing regression of the condition, or (4)relieving the conditions caused by the disease, i.e., stopping thesymptoms of the disease.

[0105] Although the examples of the present invention involve thetreatment of disorders associated with hypogonadal men, the compositionand method of the present invention may be used to treat these disordersin humans and animals of any kind, such as dogs, pigs, sheep, horses,cows, cats, zoo animals, and other commercially bred farm animals.

[0106] The present invention is further illustrated by the followingexamples, which should not be construed as limiting in any way. Thecontents of all cited references throughout this application are herebyexpressly incorporated by reference. The practice of the presentinvention will employ, unless otherwise indicated, conventionaltechniques of pharmacology and pharmaceutics, which are within the skillof the art.

EXAMPLES Example 1 Treatment of Hypogonadism in Male Subjects

[0107] One embodiment of the present invention involves the transdermalapplication of AndroGel® as a method of treating male hypogonadism. Asdemonstrated below, application of the gel results in a uniquepharmacokinetic profile for testosterone, as well as concomitantmodulation of several other sex hormones. Application of thetestosterone gel to hypogonadal male subjects also results in: (1)increased bone mineral density, (2) enhanced libido, (3) enhancederectile capability and satisfaction, (4) increased positive mood, (5)increased muscle strength, and (6) better body composition, suchincreased total body lean mass and decreased total body fat mass.Moreover, the gel is not associated with significant skin irritation.

Methods

[0108] In this example, hypogonadal men were recruited and studied in 16centers in the United States. The patients were between 19 and 68 yearsand had single morning serum testosterone levels at screening of lessthan or equal to 300 ng/dL (10.4 nmol/L). A total of 227 patients wereenrolled: 73, 78, and 76 were randomized to receive 5.0 g/day ofAndroGel® (delivering 50 mg/day of testosterone to the skin of whichabout 10% or 5 mg is absorbed), 10.0 g/day of AndroGel® (delivering 100mg/day of testosterone to the skin of which about 10% or 10 mg isabsorbed), or the ANDRODERM® testosterone patch (“T patch”) (delivering50 mg/day of testosterone), respectively.

[0109] As shown in the following table, there were no significantgroup-associated differences of the patients' characteristics atbaseline. TABLE 6 Baseline Characteristics of the Hypogonadal MenAndroGel ® AndroGel ® Treatment Group T patch (5.0 g/day) (10.0 g/day)No of subjects enrolled 76 73 78 Age (years) 51.1 51.3 51.0 Range(years) 28-67 23-67 19-68 Height (cm) 179.3 ± 0.9  175.8 ± 0.8  178.6 ±0.8  Weight (kg) 92.7 ± 1.6  90.5 ± 1.8  91.6 ± 1.5  Serum testosterone(nmol/L) 6.40 ± 0.41 6.44 ± 0.39 6.49 ± 0.37 Causes of hypogonadismPrimary hypogonadism 34 26 34 Klinefelter's Syndrome 9 5 8 PostOrchidectomy/Anorchia 2 1 3 Primary Testicular Failure 23 20 23Secondary hypogonadism 15 17 12 Kallman's Syndrome 2 2 0 HypothalimicPituitary Disorder 6 6 3 Pituitary Tumor 7 9 9 Aging 6 13 6 Notclassified 21 17 26 Years diagnosed 5.8 ± 1.1 4.4 ± 0.9 5.7 ± 1.24Number previously treated with 50 (65.8%) 38 (52.1%) 46 (59.0%)testosterone Type of Previous Hormonal Treatment Intramuscularinjections 26 20 28 Transdermal patch 12 7 8 All others 12 11 10Duration of treatment (years) 5.8 ± 1.0 5.4 ± 0.8 4.6 ± 80.7

[0110] Forty-one percent ({fraction (93/227)}) of the subjects had notreceived prior testosterone replacement therapy. Previously treatedhypogonadal men were withdrawn from testosterone ester injection for atleast six weeks and oral or transdermal androgens for four weeks beforethe screening visit. Aside from the hypogonadism, the subjects were ingood health as evidenced by medical history, physical examination,complete blood count, urinalysis, and serum biochemistry. If thesubjects were on lipid-lowering agents or tranquilizers, the doses werestabilized for at least three months prior to enrollment. Less than 5%of the subjects were taking supplemental calcium or vitamin D during thestudy. The subjects had no history of chronic medical illness, alcoholor drug abuse. They had a normal rectal examination, a PSA level of lessthan 4 ng/mL, and a urine flow rate of 12 mL/s or greater. Patients wereexcluded if they had a generalized skin disease that might affect thetestosterone absorption or prior history of skin irritability withANDRODERM® patch. Subjects weighing less than 80% or over 140% of theirideal body weight were also excluded.

[0111] The randomized, multi-center, parallel study compared two dosesof AndroGel® with the ANDRODERM® testosterone patch. The study wasdouble-blind with respect to the AndroGel® dose and open-labeled for thetestosterone patch group. For the first three months of the study (days1 to 90), the subjects were randomized to receive 5.0 g/day ofAndroGel®, 10.0 g/day of AndroGel®, or two non-scrotal patches. In thefollowing three months (days 91 to 180), the subjects were administeredone of the following treatments: 5.0 g/day of AndroGel®, 10.0 g/day ofAndroGel®, 7.5 g/day of AndroGel®, or two non-scrotal patches. Patientswho were applying AndroGel® had a single, pre-application serumtestosterone measured on day 60 and, if the levels were within thenormal range of 300 to 1,000 ng/dL (10.4 to 34.7 nmol/L), then theyremained on their original dose. Patients with testosterone levels lessthan 300 ng/dL and who were originally assigned to apply 5.0 g/day ofAndroGel® and those with testosterone levels more than 1,000 ng/dL whohad received 10.0 g/day of AndroGel® were then reassigned to administer7.5 g/day of AndroGel® for days 91 to 180.

[0112] Accordingly, at 90 days, dose adjustments were made in theAndroGel® groups based on the pre-application serum testosterone levelson day 60. Twenty subjects in the 5.0 g/day AndroGel® group had the doseincreased to 7.5 g/day. Twenty patients in the 10.0 g/day AndroGel®group had the AndroGel® dose reduced to 7.5 g/day. There were threepatients in the testosterone patch group who were switched to 5.0 g/dayAndroGel® because of patch intolerance. One 10.0 g/day AndroGel® subjectwas adjusted to receive 5.0 g/day and one 5.0 g/day AndroGel® subjecthad the dose adjusted to 2.5 g/day. The number of subjects enrolled intoday 91 to 180 of the study thus consisted of 51 receiving 5.0 g/day ofAndroGel®, 40 receiving 7.5 g/day of AndroGel®, 52 receiving 10.0 g/dayof AndroGel®, and 52 continuing on the ANDRODERM® patch. The treatmentgroups in this example may thus be characterized in two ways, either by“initial” or by the “final” treatment group.

[0113] Subjects returned to the study center on days 0, 30, 60, 90, 120,150, and 180 for a clinical examination, skin irritation and adverseevent assessments. Fasting blood samples for calcium, inorganicphosphorus, parathyroid hormone (“PTH”), osteocalcin, type Iprocollagen, and skeletal specific alkaline phosphatase (“SALP”) werecollected on days 0, 30, 90, 120, and 180. In addition, a fastingtwo-hour timed urine collection for urine creatinine, calcium, and type1 collagen cross-linked N-telopeptides (“N-telopeptide”) were collectedon days 0, 30, 90, 120, and 180. Other tests performed were as follows:

[0114] (1) Hematology: hemoglobin, hematocrit, red blood cell count,platelets, white blood cell counts with differential analysis(neutrophils, lymphocytes, monocytes, eosinophils, and basophils);

[0115] (2) Chemistry: alkaline phosphatase, alanine aminotransferase,serum glutamic pyruvic transaminase (“ALT/SGPT”), asparateaminotransferase/serum glutamin axaloacetic transaminase (“AST/SGOT”),total bilirubin, creatinine, glucose, and elecrolytes (sodium,potassium, choride, bicarbonate, calcium, and inorganic phosphorus);

[0116] (3) Lipids: total cholesterol, high-density lipoprotein (“HDL”),low-density lipoprotein (“LDL”), and triglycerides;

[0117] (4) Urinalysis: color, appearance, specific gravity, pH, protein,glucose, ketones, blood, bilirubin, and nitrites; and

[0118] (5) Other: PSA (screening days 90-180), prolactin (screening),and testosterone (screening) including electrolytes, glucose, renal, andliver function tests and lipid profile, were performed at all clinicvisits. Bone mineral density (“BMD“) was analyzed at day 0 and day 180.

A. AndroGel® and ANDRODERM® Patch

[0119] Approximately 250 g of AndroGel® was packaged in multidose glassbottles that delivered 2.25 g of the gel for each actuation of the pump.Patients assigned to apply 5.0 g/day of AndroGel® testosterone weregiven one bottle of AndroGel® and one bottle of placebo gel (containingvehicle but no testosterone), while those assigned to receive 10.0 g/dayof AndroGel® were dispensed two bottles of the active AndroGel®. Thepatients were then instructed to apply the bottle contents to the rightand left upper arms/shoulders and to the right and left sides of theabdomen on an alternate basis. For example, on the first day of thestudy, patients applied two actuations from one bottle, one each to theleft and right upper arm/shoulder, and two actuations from the secondbottle, one each to the left and right abdomen. On the following day oftreatment, the applications were reversed. Alternate application sitescontinued throughout the study. After application of the gel to theskin, the gel dried within a few minutes. Patients washed their handsthoroughly with soap and water immediately after gel application.

[0120] The 7.5 g/day AndroGel® group received their dose in anopen-label fashion. After 90 days, for the subjects titrated to theAndroGel® 7.5 g/day dose, the patients were supplied with three bottles,one containing placebo and the other two AndroGel®. The subjects wereinstructed to apply one actuation from the placebo bottle and threeactuations from a AndroGel® bottle to four different sites of the bodyas above. The sites were rotated each day taking the same sequence asdescribed above.

[0121] ANDRODERM® testosterone patches each delivering 2.5 mg/day oftestosterone were provided to about one-third of the patients in thestudy. These patients were instructed to apply two testosterone patchesto a clean, dry area of skin on the back, abdomen, upper arms, or thighsonce per day. Application sites were rotated with approximately sevendays interval between applications to the same site.

[0122] On study days when the patients were evaluated, the gel/patcheswere applied following pre-dose evaluations. On the remaining days, thetestosterone gel or patches were applied at approximately 8:00 a.m. for180 days.

B. Study Method and Results 1. Hormone Pharmacokinetics

[0123] On days 0, 1, 30, 90, and 180, the patients had multiple bloodsamples for testosterone and free testosterone measurements at 30, 15and 0 minutes before and 2, 4, 8, 12, 16, and 24 hours after AndroGel®or patch application. In addition, subjects returned on days 60, 120,and 150 for a single blood sampling prior to application of the gel orpatch. Serum DHT, E₂, FSH, LH and SHBG were measured on samplescollected before gel application on days 0, 30, 60, 90, 120, 150, and180. Sera for all hormones were stored frozen at −20° C. until assay.All samples for a patient for each hormone were measured in the sameassay whenever possible. The hormone assays were then measured at theEndocrine Research Laboratory of the UCLA-Harbor Medical Center.

[0124] The following table summarizes the pharmacokinetic parameterswere measured for each patient: TABLE 7 Pharmacokinetic ParametersAUC₀₋₂₄ area under the curve from 0 to 24 hours, determined using thelinear trapezoidal rule. C_(base) or C_(o) Baseline concentrationC_(avg) time-averaged concentration over the 24-hour dosing intervaldetermined by AUC₀₋₂₄/24 C_(max) maximum concentration during the24-hour dosing interval C_(min) minimum concentration during the 24-hourdosing interval T_(max) time at which C_(max) occurred T_(min) time atwhich C_(min) occurred Fluctuation extent of variation in the serumconcentration over the course of a single Index day, calculated as(C_(max) − C_(min))/C_(avg) Accumulation increase in the daily drugexposure with continued dosing, calculated as ratio the ratio of the AUCat steady on a particular day over the AUC on day 1 (e.g.,AUC_(day 30)/AUC_(day 1)) Net AUC₀₋₂₄ AUC₀₋₂₄ on days 30, 90, 180 -AUC₀₋₂₄ on day 0

a. Testosterone Pharmacokinetics (1) Methods

[0125] Serum testosterone levels were measured after extraction withethylacetate and hexane by a specific radioimmunoassay (“RIA”) usingreagents from ICN (Costa Mesa, Calif.). The cross reactivities of theantiserum used in the testosterone RIA were 2.0% for DHT, 2.3% forandrostenedione, 0.8% for 3-β-androstanediol, 0.6% for etiocholanoloneand less than 0.01% for all other steroids tested. The lower limit ofquantitation (“LLQ”) for serum testosterone measured by this assay was25 ng/dL (0.87 nmol/L). The mean accuracy of the testosterone assay,determined by spiking steroid free serum with varying amounts oftestosterone (0.9 nmol/L to 52 nmol/L), was 104% and ranged from 92% to117%. The intra-assay and inter-assay coefficients of the testosteroneassay were 7.3 and 11.1%, respectively, at the normal adult male range.In normal adult men, testosterone concentrations range from 298 to 1,043ng/dL (10.33 to 36.17 nmol/L) as determined at the UCLA-Harbor MedicalCenter.

(2) Baseline Concentration

[0126] As shown in Table 8 and FIG. 5(a), at baseline, the average serumtestosterone concentrations over 24 hours (C_(avg)) were similar in thegroups and below the adult normal range. Moreover the variations of theserum concentration (based on maximum and minimum concentrations duringthe 24-hour period, C_(max) and C_(min), respectively) during the daywere also similar in the three groups. FIG. 5(a) shows that the meantestosterone levels had a the maximum level between 8 to 10 a.m. (i.e.,at 0 to 2 hours) and the minimum 8 to 12 hours later, demonstrating amild diurnal variation of serum testosterone. About one-third of thepatients in each group had C_(avg) within the lower normal adult malerange on day 0 (24/73 for the 5.0 g/day AndroGel® group, 26/78 for the10.0 g/day AndroGel® group, and 25/76 for testosterone patch group). Allexcept three of the subjects met the enrollment criterion of serumtestosterone less than 300 ng/dL (10.4 nmol/L) on admission. TABLE 8(a)Baseline Phamacokinetic Parameters by Initial Treatment Group (Mean ±SD) 5.0 g/day T-Gel 10.0 g/day T-gel T-patch N 73 78 76 C_(avg) (ng/dL)237 ± 130 248 ± 140 237 ± 139 C_(max) (ng/dL) 328 ± 178 333 ± 194 314 ±179 T_(max) *(hr)  4.0 (0.0-24.5) 7.9 (0.0-24.7) 4.0 (0.0-24.3) C_(min)(ng/dL) 175 ± 104 188 ± 112 181 ± 112 T_(min) *(hr) 8.01 (0.0-24.1) 8.0(0.0-24.0) 8.0 (0.0-23.9) Fluc Index (ratio) 0.627 ± 0.479 0.556 ± 0.3840.576 ± 0.341

[0127] TABLE 8(b) Baseline Testosterone Pharmacokinetic Parameters byFinal Treatment Group (Mean ± SD) Doses Received During Initial =>Extended Treatment Phases 5.0 g/day 5.0 => 7.5 g/day 10.0 => 7.5 g/day10.0 g/day T-gel T-gel T-gel T-gel T-patch N 53 20 20 58 76 C_(avg)(ng/dL) 247 ± 137 212 ± 109 282 ± 157 236 ± 133 237 ± 140 C_(max)(ng/dL) 333 ± 180 313 ± 174 408 ± 241 307 ± 170 314 ± 179 T_(max)* (hr)4.0 (0.0-24.5)  4.0 (0.0-24.0) 19.7 (0.0-24.3) 4.0 (0.0-24.7) 4.0(0.0-24.3) C_(min) (ng/dL) 185 ± 111 150 ± 80  206 ± 130 182 ± 106 181 ±112 T_(min)* (hr) 8.0 (0.0-24.1) 11.9 (0.0-24.0)  8.0 (0.0-23.3) 8.0(0.0-24.0) 8.0 (0.0-23.9) Fluc Index (ratio) 0.600 ± 0.471 0.699 ± 0.5030.678 ± 0.580 0.514 ± 0.284 0.576 ± 0.341

(3) Day 1

[0128]FIG. 5(b) and Tables 8(c)-(d) show the pharmacokinetic profile forall three initial treatment groups after the first application oftransdermal testosterone. In general, treatment with AndroGel® and thetestosterone patch produced increases in testosterone concentrationssufficiently large to bring the patients into the normal range in just afew hours. However, even on day 1, the pharmacokinetic profiles weremarkedly different in the AndroGel® and patch groups. Serum testosteronerose most rapidly in the testosterone patch group reaching a maximumconcentration (C_(max)) at about 12 hours (T_(max)). In contrast, serumtestosterone rose steadily to the normal range after AndroGel®application with C_(max) levels achieved by 22 and 16 hours in the 5.0g/day AndroGel® group and the 10.0 g/day AndroGel® group, respectively.TABLE 8(c) Testosterone Pharmacokinetic Parameters on Day 1 by InitialTreatment Group (Mean ± SD) 5.0 g/day T-Gel 10.0 g/day T-gel T-patch N73 76 74 C_(avg) (ng/dL) 398 ± 156 514 ± 227 482 ± 204 C_(max) (ng/dL)560 ± 269 748 ± 349 645 ± 280 T_(max) *(hr) 22.1 (0.0-25.3) 16.0(0.0-24.3) 11.8 (1.8-24.0) C_(min) (ng/dL) 228 ± 122 250 ± 143 232 ± 132T_(min) *(hr)  1.9 (0.0-24.0) 0.0 (0.0-24.2)  1.5 (0.0-24.0)

[0129] TABLE 8(d) Testosterone Phamacokinetic Parameters on Day 1 byFinal Treatment Group (Mean ± SD) Doses Received During Initial =>Extended Treatment Phases 5.0 g/day 5.0 => 7.5 g/day 10.0 => 7.5 g/day10.0 g/day T-gel T-gel T-gel T-gel T-patch N 53 20 19 57 74 C_(avg)(ng/dL) 411 ± 160 363 ± 143 554 ± 243 500 ± 223 482 ± 204 C_(max)(ng/dL) 573 ± 285 525 ± 223 819 ± 359 724 ± 346 645 ± 280 T_(max)* (hr)22.1 (0.0-25.3) 19.5 (1.8-24.3) 15.7 (3.9-24.0) 23.0 (0.0-24.3) 11.8(1.8-24.0) C_(min) (ng/dL) 237 ± 125 204 ± 112 265 ± 154 245 ± 140 232 ±132 T_(min)* (hr)  1.8 (0.0-24.0)  3.5 (0.0-24.0)  1.9 (0.0-24.2)  0.0(0.0-23.8)  1.5 (0.0-24.0) Fluc Index (ratio) 0.600 ± 0.471 0.699 ±0.503 0.678 ± 0.580 0.514 ± 0.284 0.576 ± 0.341

(4) Days 30,90, and 180

[0130] FIGS. 5(c) and 5(d) show the unique 24-hour pharmacokineticprofile of AndroGel®-treated patients on days 30 and 90. In theAndroGel® groups, serum testosterone levels showed small and variableincreases shortly after dosing. The levels then returned to a relativelyconstant level. In contrast, in the testosterone patch group, patientsexhibited a rise over the first 8 to 12 hours, a plateau for another 8hours, and then a decline to the baseline of the prior day. Further,after gel application on both days 30 and 90, the C_(avg) in the 10.0g/day AndroGel® group was 1.4 fold higher than in the 5.0 g/dayAndroGel® group and 1.9 fold higher than the testosterone patch group.The testosterone patch group also had a C_(min) substantially below thelower limit of the normal range. On day 30, the accumulation ratio was0.94 for testosterone patch group, showing no accumulation. Theaccumulation ratios at 1.54 and 1.9 were significantly higher in the 5.0g/day AndroGel® group and 10.0 g/day AndroGel® group, respectively. Thedifferences in accumulation ratio among the groups persisted on day 90.This data indicates that the AndroGel® preparations had a longereffective half-life than testosterone patch.

[0131]FIG. 5(e) shows the 24-hour pharmacokinetic profile for thetreatment groups on day 180. In general, as Table 8(e) shows, the serumtestosterone concentrations achieved and the pharmacokinetic parameterswere similar to those on days 30 and 90 in those patients who continuedon their initial randomized treatment groups. Table 8(f) shows that thepatients titrated to the 7.5 g/day AndroGel® group were not homogeneous.The patients that were previously in the 10.0 g/day group tended to havehigher serum testosterone levels than those previously receiving 5.0g/day. On day 180, the C_(avg) in the patients in the 10.0 g/day groupwho converted to 7.5 g/day on day 90 was 744 ng/dL, which was 1.7 foldhigher than the. C_(avg) of 450 ng/dL in the patients titrated to 7.5g/day from 5.0 g/day. Despite adjusting the dose up by 2.5 g/day in the5.0 to 7.5 g/day group, the C_(avg) remained lower than those remainingin the 5.0 g/day group. In the 10.0 to 7.5 g/day group, the C_(avg)became similar to those achieved by patients remaining in the 10.0 g/daygroup without dose titration. These results suggest that many of theunder-responders may actually be poorly compliant patients. For example,if a patient does not apply AndroGel® properly (e.g., preferentiallyfrom the placebo container or shortly before bathing), then increasingthe dose will not provide any added benefit.

[0132] FIGS. 5(f)-(h) compare the pharmacokinetic profiles for the 5.0g/day AndroGel® group, the 10.0 AndroGel® g/day group, and thetestosterone patch group at days 0, 1, 30, 90, and 180, respectively. Ingeneral, the mean serum testosterone levels in the testosterone patchgroup remained at the lower limit of the normal range throughout thetreatment period. In contrast, the mean serum testosterone levelsremained at about 490-570 ng/dL for the 5.0 g/day AndroGel® group andabout 630-860 ng/dL AndroGel® for the 10.0 g/day group. TABLE 8(e)Testosterone Phamacokinetic Parameters on Day 1 by Initial TreatmentGroup (Mean ± SD) 5.0 g/day T-Gel 10.0 g/day T-gel T-patch Day 30 N = 66N = 74 N = 70 C_(avg) (ng/dL) 566 ± 262 792 ± 294 419 ± 163 C_(max)(ng/dL) 876 ± 466 1200 ± 482  576 ± 223 T_(max) *(hr) 7.9 (0.0-24.0) 7.8(0.0-24.3) 11.3 (0.0-24.0) C_(min) (ng/dL) 361 ± 149 505 ± 233 235 ± 122T_(min) *(hr) 8.0 (0.0-24.1) 8.0 (0.0-25.8) 2.0 (0.0-24.2) Fluc Index0.857 ± 0.331 0.895 ± 0.434 0.823 ± 0.289 (ratio) Accum Ratio 1.529 ±0.726 1.911 ± 1.588 0.937 ± 0.354 (ratio) Day 90 N = 65 N = 73 N = 64C_(avg) (ng/dL) 553 ± 247 792 ± 276 417 ± 157 C_(max) (ng/dL) 846 ± 4441204 ± 570  597 ± 242 T_(max) *(hr) 4.0 (0.0-24.1) 7.9 (0.0-25.2) 8.1(0.0-25.0) C_(min) (ng/dL) 354 ± 147 501 ± 193 213 ± 105 T_(min) *(hr)4.0 (0.0-25.3) 8.0 (0.0-24.8) 2.0 (0.0-24.0) Fluc Index 0.851 ± 0.4020.859 ± 0.399 0.937 ± 0.442 (ratio) Accum Ratio 1.615 ± 0.859 1.927 ±1.310 0.971 ± 0.453 (ratio) Day 180 N = 63 N = 68 N = 45 C_(avg) (ng/dL)520 ± 227 722 ± 242 403 ± 163 C_(max) (ng/dL) 779 ± 359 1091 ± 437  580± 240 T_(max) *(hr) 4.0 (0.0-24.0) 7.9 (0.0-24.0) 10.0 (0.0-24.0) C_(min) (ng/dL) 348 ± 164 485 ± 184 223 ± 114 T_(min) *(hr) 11.9(0.0-24.0)  11.8 (0.0-27.4)  2.0 (0.0-25.7) Fluc Index 0.845 ± 0.3790.829 ± 0.392 0.891 ± 0.319 (ratio) Accum Ratio 1.523 ± 1.024 1.897 ±2.123 0.954 ± 0.4105 (ratio)

[0133] TABLE 8(f) Testosterone Phamacokinetic Parameters on Days 30, 90,180 by Final Treatment Group (Mean ± SD) Doses Received During Initial=> Extended Treatment Phases 5.0 g/day 5.0 => 7.5 g/day 10.0 => 7.5g/day 10.0 g/day T-gel T-gel T-gel T-gel T-patch Day 30 N = 47 N = 19 N= 19 N = 55 N = 70 C_(avg) (ng/dL) 604 ± 288 472 ± 148 946 ± 399 739 ±230 419 ± 163 C_(max) (ng/dL) 941 ± 509 716 ± 294 1409 ± 556  1128 ±436  576 ± 223 T_(max)* (hr)  7.9 (0.0-24.0) 8.0 (0.0-24.0)  8.0(0.0-24.3) 7.8 (0.0-24.3) 11.3 (0.0-24.0)  C_(min) (ng/dL) 387 ± 159 296± 97  600 ± 339 471 ± 175 235 ± 122 T_(min)* (hr)  8.1 (0.0-24.1) 1.7(0.0-24.1) 11.4 (0.0-24.1) 8.0 (0.0-25.8) 2.0 (0.0-24.2) Fluc Index(ratio) 0.861 ± 0.341 0.846 ± 0.315 0.927 ± 0.409 0.884 ± 0.445 0.823 ±0.289 Accum Ratio (ratio) 1.543 ± 0.747 1.494 ± 0.691 2.053 ± 1.3931.864 ± 1.657 0.937 ± 0.354 Day 90 N = 45 N = 20 N = 18 N = 55 N = 64C_(avg) (ng/dL) 596 ± 266 455 ± 164 859 ± 298 771 ± 268 417 ± 157C_(max) (ng/dL) 931 ± 455 654 ± 359 1398 ± 733  1141 ± 498  597 ± 242T_(max)* (hr)  3.8 (0.0-24.1) 7.7 (0.0-24.0)  7.9 (0.0-24.0) 7.9(0.0-25.2) 8.1 (0.0-25.0) C_(min) (ng/dL) 384 ± 147 286 ± 125 532 ± 181492 ± 197 213 ± 105 T_(min)* (hr)  7.9 (0.0-25.3) 0.0 (0.0-24.0) 12.0(0.0-24.1) 4.0 (0.0-24.8) 2.0 (0.0-24.0) Fluc Index (ratio) 0.886 ±0.391 0.771 ± 0.425 0.959 ± 0.490 0.826 ± 0.363 0.937 ± 0.442 AccumRatio (ratio) 1.593 ± 0.813 1.737 ± 1.145 1.752 ± 0.700 1.952 ± 1.3800.971 ± 0.453 Day 180 N = 44 N = 18 N = 19 N = 48 N = 41 C_(avg) (ng/dL)555 ± 225 450 ± 219 744 ± 320 713 ± 209 408 ± 165 C_(max) (ng/dL) 803 ±347 680 ± 369 1110 ± 468  1083 ± 434  578 ± 245 T_(max)* (hr)  5.8(0.0-24.0) 2.0 (0.0-24.0)  7.8 (0.0-24.0) 7.7 (0.0-24.0) 10.6(0.0-24.0)  C_(min) (ng/dL) 371 ± 165 302 ± 150 505 ± 233 485 ± 156 222± 116 T_(min)* (hr) 11.9 (0.0-24.0) 9.9 (0.0-24.0) 12.0 (0.0-24.0) 8.0(0.0-27.4) 2.0 (0.0-25.7) Fluc Index (ratio) 0.853 ± 0.402 0.833 ± 0.3350.824 ± 0.298 0.818 ± 0.421 0.866 ± 0.311 Accum Ratio (ratio) 1.541 ±0.917 NA NA 2.061 ± 2.445 0.969 ± 0.415

(5) Dose Proportionality for AndroGel®

[0134] Table 8(g) shows the increase in AUC₀₋₂₄ on days 30, 90, and 180from the pretreatment baseline (net AUC₀₋₂₄). In order to assessdose-proportionality, the bioequivalence assessment was performed on thelog-transformed AUCs using “treatment” as the only factor. The AUCs werecompared after subtracting away the AUC contribution from the endogenoussecretion of testosterone (the AUC on day 0) and adjusting for thetwo-fold difference in applied doses. The AUC ratio on day 30 was 0.95(90% C.I.: 0.75-1.19) and on day 90 was 0.92 (90% C.I.: 73-1.17). Whenthe day 30 and day 90 data was combined, the AUC ratio was 0.93 (90%C.I.: 0.79-1.10).

[0135] The data shows dose proportionality for AndroGel® treatment. Thegeometric mean for the increase in AUC₀₋₂₄ from day 0 to day 30 or day90 was twice as great for the 10.0 g/day group as for the 5.0 g/daygroup. A 125 ng/dL mean increase in serum testosterone C_(avg) level wasproduced by each 2.5 g/day of AndroGel®. In other words, the data showsthat 0.1 g/day of AndroGel® produced, on the average, a 5 ng/dL increasein serum testosterone concentration. This dose proportionality aidsdosing adjustment by the physician. Because AndroGel® is provided in 2.5g packets (containing 25 mg of testosterone), each 2.5 g packet willproduce, on average, a 125 ng/dL increase in the C_(avg) for serum totaltestosterone. TABLE 8(g) Net AUC₀₋₂₄ (nmol*h/L) on Days 30, 90, and 180after Transdermal Testosterone Application T Patch T gel 5.0 g/day T gel10.0 g/day Day 30 154 ± 18 268 ± 28 446 ± 30 Day 90 157 ± 20 263 ± 29461 ± 28 Day 180 160 ± 25 250 ± 32 401 ± 27

[0136] The increase in AUC₀₋₂₄ from pretreatment baseline achieved bythe 10.0 g/day and the 5.0 g/day groups were approximately 2.7 and 1.7fold higher than that resulting from application of the testosteronepatch.

b. Pharmacokinetics of Serum Free Testosterone Concentration (1) Methods

[0137] Serum free testosterone was measured by RIA of the dialysate,after an overnight equilibrium dialysis, using the same RIA reagents asthe testosterone assay. The LLQ of serum free testosterone, using theequilibrium dialysis method, was estimated to be 22 pmol/L. When steroidfree serum was spiked with increasing doses of testosterone in the adultmale range, increasing amounts of free testosterone were recovered witha coefficient of variation that ranged from 11.0-18.5%. The intra- andinterassay coefficients of free testosterone were 15% and 16.8% foradult normal male values, respectively. As estimated by the UCLA-HarborMedical Center, free testosterone concentrations range from 3.48-17.9ng/dL (121-620 pmol/L) in normal adult men.

(2) Pharmacokinetic Results

[0138] In general, as shown in Table 9, the pharmacokinetic parametersof serum free testosterone mirrored that of serum total testosterone asdescribed above. At baseline (day 0), the mean serum free testosteroneconcentrations (C_(avg)) were similar in all three groups which were atthe lower limit of the adult male range. The maximum serum freetestosterone concentration occurred between 8 and 10 a.m., and theminimum about 8 to 16 hours later. This data is consistent with the milddiurnal variation of serum testosterone.

[0139]FIG. 6(a) shows the 24-hour pharmacokinetic profiles for the threetreatment groups on day 1. After application of the testosterone patch,the serum free testosterone levels peaked at 12 hours about 4 hoursearlier than those achieved by the AndroGel® groups The serum freetestosterone levels then declined in the testosterone patch groupwhereas in the AndroGel® groups, the serum free testosterone levelscontinued to rise.

[0140] FIGS. 6(b) and 6(c) show the pharmacokinetic profiles of freetestosterone in the AndroGel®-treated groups resembled the uniquetestosterone profiles on days 30 and 90. After AndroGel® application,the mean serum free testosterone levels in the three groups were withinnormal range. Similar to the total testosterone results, the freetestosterone C_(avg) achieved by the 10.0 g/day group was 1.4 foldhigher than the 5.0 g/day group and 1.7 fold higher than thetestosterone patch group. Moreover, the accumulation ratio for thetestosterone patch was significantly less than that of the 5.0 g/dayAndroGel® group and the 10.0 g/day AndroGel® group.

[0141]FIG. 6(d) shows the free testosterone concentrations by finaltreatment groups on day 180. In general, the free testosteroneconcentrations exhibited a similar pattern as serum testosterone. The24-hour pharmacokinetic parameters were similar to those on days 30 and90 in those subjects who remained in the three original randomizedgroups. Again, in the subjects titrated to receive 7.5 g/day ofAndroGel®, the group was not homogenous. The free testosterone C_(avg)in the patients with doses adjusted upwards from 5.0 to 7.5 g/dayremained 29% lower than those of subjects remaining in the 5.0 g/daygroup. The free testosterone C_(avg) in the patients whose doses weredecreased from 10.0 to 7.5 g/day was 11% higher than those in remainingin the 10.0 g/day group.

[0142] FIGS. 6(e)-(g) show the free testosterone concentrations in thethree groups of subjects throughout the 180-day treatment period. Again,the free testosterone levels followed that of testosterone. The meanfree testosterone levels in all three groups were within the normalrange with the 10.0 g/day group maintaining higher free testosteronelevels than both the 5.0 g/day and the testosterone patch groups. TABLE9 Free Testosterone Pharmacokinetic Parameters by Final Treatment (Mean± SD) Doses Received During Initial => Extended Treatment Phases 5.0g/day 5.0 => 7.5 g/day 10.0 => 7.5 g/day 10/0 g/day T-gel T-gel T-gel Tgel T-patch Day 0 N = 53 N = 20 N = 20 N = 58 N = 76 Cavg (ng/dL) 4.52 ±3.35 4.27 ± 3.45 4.64 ± 3.10 4.20 ± 3.33 4.82 ± 3.64 Cmax (ng/dL) 5.98 ±4.25 6.06 ± 5.05 6.91 ± 4.66 5.84 ± 4.36 6.57 ± 4.90 Tmax* (hr)  4.0(0.0-24.5)  2.0 (0.0-24.0) 13.5 (0.0-24.2)  2.1 (0.0-24.1)  3.8(0.0-24.0) Cmin (ng/dL) 3.23 ± 2.74 3.10 ± 2.62 3.14 ± 2.14 3.12 ± 2.683.56 ± 2.88 Tmin* (hr)  8.0 (0.0-24.2)  9.9 (0.0-16.0)  4.0 (0.0-23.3) 8.0 (0.0-24.0)  7.9 (0.0-24.0) Fluc Index (ratio) 0.604 ± 0.342 0.674 ±0.512 0.756 ± 0.597 0.634 ± 0.420 0.614 ± 0.362 Day 1 N= 53 N= 20 N = 19N = 57 N = 74 Cavg (ng/dL) 7.50 ± 4.83 6.80 ± 4.82 9.94 ± 5.04 8.93 ±6.09 9.04 ± 4.81 Cmax (ng/dL) 10.86 ± 7.45  10.10 ± 7.79  15.36 ± 7.31 13.20 ± 8.61  12.02 ± 6.14  Tmax* (hr) 16.0 (0.0-25.3) 13.9 (0.0-24.3)15.7 (2.0-24.0) 23.5 (1.8-24.3) 12.0 (1.8-24.0) Cmin (ng/dL) 4.30 ± 3.333.69 ± 3.24 3.88 ± 2.73 4.40 ± 3.94 4.67 ± 3.52 Tmin* (hr)  0.0(0.0-24.1)  1.8 (0.0-24.0)  0.0 (0.0-24.2)  0.0 (0.0-23.9)  0.0(0.0-24.0) Day 30 N= 47 N = 19 N = 19 N = 55 N = 70 Cavg (ng/dL) 11.12 ±6.22  7.81 ± 3.94 16.18 ± 8.18  13.37 ± 7.13  8.12 ± 4.15 Cmax (ng/dL)16.93 ± 10.47 11.62 ± 6.34  25.14 ± 10.80 19.36 ± 9.75  11.48 ± 5.78 Tmax* (hr)  8.0 (0.0-27.8)  8.0 (0.0-26.3)  8.0 (0.0-24.3)  8.0(0.0-24.3)  8.0 (0.0-24.0) Cmin (ng/dL) 6.99 ± 3.82 4.78 ± 3.10 9.99 ±7.19 8.25 ± 5.22 4.31 ± 3.20 Tmin* (hr)  4.0 (0.0-24.1)  3.5 (0.0-24.1)11.4 (0.0-24.1)  7.8 (0.0-25.8)  2.0 (0.0-24.8) Flue Index (ratio) 0.853± 0.331 0.872 ± 0.510 1.051 ± 0.449 0.861 ± 0.412 0.929 ± 0.311 AccumRatio (ratio) 1.635 ± 0.820 1.479 ± 0.925 2.065 ± 1.523 1.953 ± 1.6260.980 ± 0.387 Day 90 N = 45 N = 20 N = 18 N = 55 N = 64 Cavg (ng/dL)12.12 ± 7.78 8.06 ± 3.78 17.65 ± 8.62  13.11 ± 5.97  8.50 ± 5.04 Cmax(ng/dL) 18.75 ± 12.90 10.76 ± 4.48  25.29 ± 12.42 18.61 ± 8.20  12.04 ±6.81  Tmax* (hr)  4.0 (0.0-24.0)  9.7 (0.0-24.0)  8.0 (0.0-24.0)  8.0(0.0-25.2) 11.6 (0.0-25.0) Cmin (ng/dL) 7.65 ± 4.74 4.75 ± 2.86 10.56 ±6.07  8.40 ± 4.57 4.38 ± 3.70 Tmin* (hr)  8.0 (0.0-24.0)  1.9 (0.0-24.0) 5.9 (0.0-24.1)  4.0 (0.0-24.8)  2.0 (0.0-24.1) Fluc Index (ratio) 0.913± 0.492 0.815 ± 0.292 0.870 ± 0.401 0.812 ± 0.335 0.968 ± 0.402 AccumRatia (ratio) 1.755 ± 0.983 1.916 ± 1.816 1.843 ± 0.742 2.075 ± 1.8661.054 ± 0.498 Day 180 N = 44 N = 18 N = 19 N = 48 N = 41 Cavg (ng/dL)11.01 ± 5.24  7.80 ± 4.63 14.14 ± 7.73  12.77 ± 5.70  7.25 ± 4.90 Cmax(ng/dL) 16.21 ± 7.32  11.36 ± 6.36  22.56 ± 12.62 18.58 ± 9.31  10.17 ±5.90  Tmax* (hr)  7.9 (0.0-24.0)  2.0 (0.0-23.9)  7.8 (0.0-24.0)  8.0(0.0-24.0) 11.1 (0.0-24.0) Cmin (ng/dL) 7.18 ± 3.96 5.32 ± 4.06 9.54 ±6.45 8.23 ± 4.01 3.90 ± 4.20 Tmin* (hr)  9.9 (0.0-24.2)  7.9 (0.0-24.0) 8.0 (0.0-23.2) 11.8 (0.0-27.4)  2.5 (0.0-25.7) Fluc Index (ratio) 0.897± 0.502 0.838 ± 0.378 0.950 ± 0.501 0.815 ± 0.397 0.967 ± 0.370 AccumRatio (ratio) 1.712 ± 1.071 NA NA 2.134 ± 1.989 1.001 ± 0.580

c. Serum DHT Concentrations

[0143] Serum DHT was measured by RIA after potassium permanganatetreatment of the sample followed by extraction. The methods and reagentsof the DHT assay were provided by DSL (Webster, Tex.). The crossreactivities of the antiserum used in the RIA for DHT were 6.5% for3-β-androstanediol, 1.2% for 3-α-androstanediol, 0.4% for3-α-androstanediol glucuronide, and 0.4% for testosterone (afterpotassium permanganate treatment and extraction), and less than 0.01%for other steroids tested. This low cross-reactivity againsttestosterone was further confirmed by spiking steroid free serum with 35nmol/L (1,000 pg/dL) of testosterone and taking the samples through theDHT assay. The results even on spiking with over 35 nmol/L oftestosterone was measured as less than 0.1 nmol/L of DHT. The LLQ ofserum DHT in the assay was 0.43 nmol/L. The mean accuracy (recovery) ofthe DHT assay determined by spiking steroid free serum with varyingamounts of DHT from 0.43 nmol/L to 9 nmol/L was 101% and ranged from 83to 114%. The intra-assay and inter-assay coefficients of variation forthe DHT assay were 7.8 and 16.6%, respectively, for the normal adultmale range. The normal adult male range of DHT was 30.7-193.2 ng/dL(1.06 to 6.66 nmol/L ) as determined by the UCLA-Harbor Medical Center.

[0144] As shown in Table 10, the pretreatment mean serum DHTconcentrations were between 36 and 42 ng/dL, which were near the lowerlimit of the normal range in all three initial treatment groups. None ofthe patients had DHT concentrations above the upper limit of the normalrange on the pretreatment day, although almost half (103 patients) hadconcentrations less than the lower limit.

[0145]FIG. 7 shows that after treatment, the differences between themean DHT concentrations associated with the different treatment groupswere statistically significant, with patients receiving AndroGel® havinga higher mean DHT concentration than the patients using the patch andshowing dose-dependence in the mean serum DHT concentrations.Specifically, after testosterone patch application mean serum DHT levelsrose to about 1.3 fold above the baseline. In contrast, serum DHTincreased to 3.6 and 4.8 fold above baseline after application of 5.0g/day and 10.0 g/day of AndroGel® respectively. TABLE 10 DHTConcentrations (ng/dL) on Each of the Observation Days By InitialTreatment (Mean ± SD) Day 0 Day 30 Day 60 Day 90 Day 120 Day 150 Day 180 5.0 g/day N = 73 N = 69 N = 70 N = 67 N = 65 N = 63 N = 65 T-gel 36.0 ±19.9 117.6 ± 74.9  122.4 ± 99.4  130.1 ± 99.2  121.8 ± 89.2  144.7 ±110.5 143.7 ± 105.9 10.0 g/day N = 78 N = 78 N = 74 N = 75 N = 68 N = 67N = 71 T-gel 42.0 ± 29.4 200.4 ± 127.8 222.0 ± 126.6 207.7 ± 111.0 187.3± 97.3  189.1 ± 102.4 206.1 ± 105.9 T-Patch N = 76 N = 73 N = 68 N = 66N = 49 N = 46 N = 49 37.4 ± 21.4 50.8 ± 34.6 49.3 ± 27.2 43.6 ± 26.953.0 ± 52.8 54.0 ± 42.5 52.1 ± 34.3 Across RX 0.6041 0.0001 0.00010.0001 0.0001 0.0001 0.0001

[0146] The increase in DHT concentrations are likely attributed to theconcentration and location of 5α-reductase in the skin. For example, thelarge amounts of 5α-reductase in the scrotal skin presumably causes anincrease in DHT concentrations in the TESTODERM® patch. In contrast, theANDRODERM® and TESTODERM TTS® patches create little change in DTH levelsbecause the surface area of the patch is small and little 5α-reductaseis located in nonscrotal skin. AndroGel® presumably causes an increasein DHT levels because the gel is applied to a relatively large skin areaand thus exposes testosterone to greater amounts of the enzyme.

[0147] To date, elevated DHT levels have not been reported to have anyadverse clinical effects. Moreover, there is some evidence to suggestthat increased DHT levels may inhibit prostate cancer.

d. DHT/T Ratio

[0148] The UCLA-Harbor Medical Center reports a DHT/T ratio of0.052-0.328 for normal adult men. In this example, the mean ratios forall three treatments were within the normal range on day 0. As shown inFIG. 8 and Table 11, there were treatment and concentration-dependentincreases observed over the 180-day period. Specifically, the AndroGel®treatment groups showed the largest increase in DHT/T ratio. However,the mean ratios for all of the treatment groups remained within thenormal range on all observation days. TABLE 11 DHT/T Ratio on Each ofthe Observation Days By Initial Treatment (Mean ± SD) Day 0 Day 30 Day60 Day 90 Day 120 Day 150 Day 180  5.0 g/day N = 73 N = 68 N = 70 N = 67N = 65 N = 62 N = 64 T-gel 0.198 ± 0.137 0.230 ± 0.104 0.256 ± 0.1320.248 ± 0.121 0.266 ± 0.119 0.290 ± 0.145 0.273 ± 0.160 10.0 g/day N =78 N = 77 N = 74 N = 74 N = 68 N = 67 N = 71 T-gel 0.206 ± 0.163 0.266 ±0.124 0.313 ± 0.160 0.300 ± 0.131 0.308 ± 0.145 0.325 ± 0.142 0.291 ±0.124 T-Patch N = 76 N = 73 N = 68 N = 65 N = 49 N = 46 N = 46 0.204 ±0.135 0.192 ± 0.182 0.175 ± 0.102 0.175 ± 0.092 0.186 ± 0.134 0.223 ±0.147 0.212 ± 0.160 Across RX 0.7922 0.0001 0.0001 0.0001 0.0001 0.00010.0002

e. Total Androgen (DHT+T)

[0149] The UCLA-Harbor Medical Center has determined that the normaltotal androgen concentration is 372 to 1,350 ng/dL. As shown in FIG. 9and Table 12, the mean pre-dose total androgen concentrations for allthree treatments were below the lower limit of the normal range onpretreatment day 0. The total androgen concentrations for both AndroGel®groups were within the normal range on all treatment observation days.In contrast, the mean concentrations for patients receiving thetestosterone patch was barely within the normal range on day 60 and 120,but were below the lower normal limit on days 30, 90, 150, and 180.TABLE 12 Total Androgen (DHT + T) (ng/dL) on Each of the ObservationDays By Initial Treatment (Mean ± SD) Day 0 Day 30 Day 60 Day 90 Day 120Day 150 Day 180  5.0 g/day N = 73 N = 68 N = 70 N = 67 N = 65 N = 62 N =64 T-gel 281 ± 150 659 ± 398 617 ± 429 690 ± 431 574 ± 331 631 ± 384 694± 412 10.0 g/day N = 78 N = 77 N = 74 N = 74 N = 68 N = 67 N = 71 T-gel307 ± 180 974 ± 532 1052 ± 806  921 ± 420 827 ± 361 805 ± 383 944 ± 432T-Patch N = 76 N = 73 N = 68 N = 65 N = 49 N = 46 N = 46 282 ± 159 369 ±206 392 ± 229 330 ± 173 378 ± 250 364 ± 220 355 ± 202 Across RX 0.73950.0001 0.0001 0.0001 0.0001 0.0001 0.0001

f. E₂ Concentrations

[0150] Serum E₂ levels were measured by a direct assay withoutextraction with reagents from ICN (Costa Mesa, Calif.). The intra-assayand inter-assay coefficients of variation of E₂ were 6.5 and 7.1%respectively. The UCLA-Harbor Medical Center reported an average E₂concentration ranging from 7.1 to 46.1 pg/mL (63 to 169 pmol/L) fornormal adult male range. The LLQ of the E₂ was 18 pmol/L. The crossreactivities of the E₂ antibody were 6.9% for estrone, 0.4% forequilenin, and less than 0.01% for all other steroids tested. Theaccuracy of the E₂ assay was assessed by spiking steroid free serum withincreasing amount of E₂ (18 to 275 pmol/L). The mean recovery of E₂compared to the amount added was 99.1% and ranged from 95 to 101%.

[0151]FIG. 10 depicts the E₂ concentrations throughout the 180-daystudy. The pretreatment mean E₂ concentrations for all three treatmentgroups were 23-24 pg/mL. During the study, the E₂ levels increased by anaverage 9.2% in the testosterone patch during the treatment period,30.9% in the 5.0 g/day AndroGel® group, and 45.5% in the 10.0 g/dayAndroGel® group. All of the mean concentrations fell within the normalrange. TABLE 13 Estradiol Concentration (pg/mL) on Each of theObservation Days By Initial Treatment (Mean ± SD) Day 0 Day 30 Day 60Day 90 Day 120 Day 150 Day 180  5.0 g/day T-gel N = 73 N = 69 N = 68 N =67 N = 64 N = 65 N = 65 23.0 ± 9.2 29.2 ± 11.0 28.1 ± 10.0 31.4 ± 11.928.8 ± 9.9  30.8 ± 12.5 32.3 ± 13.8 10.0 g/day T-gel N = 78 N = 78 N =74 N = 75 N = 71 N = 66 N = 71 24.5 ± 9.5 33.7 ± 11.5 36.5 ± 13.5 37.8 ±13.3 34.6 ± 10.4 35.0 ± 11.1 36.3 ± 13.9 T-Patch N = 76 N = 72 N = 68 N= 66 N = 50 N = 49 N = 49 23.8 ± 8.2 25.8 ± 9.8  24.8 ± 8.0  25.7 ± 9.8 25.7 ± 9.4  27.0 ± 9.2  26.9 ± 9.5  Across RX 0.6259 0.0001 0.00010.0001 0.0001 0.0009 0.0006

[0152] E₂ is believed to be important for the maintenance of normalbone. In addition, E₂ has a positive effect on serum lipid profiles.

g. Serum SHBG Concentrations

[0153] Serum SHBG levels were measured with a fluoroimmunometric assay(“FIA”) obtained from Delfia (Wallac, Gaithersberg, Md.). The intra- andinterassay coefficients were 5% and 12% respectively. The LLQ was 0.5nmol/L. The UCLA-Harbor Medical Center determined that the adult normalmale range for the SHBG assay is 0.8 to 46.6 nmol/L.

[0154] As shown in FIG. 11 and Table 11, the serum SHBG levels weresimilar and within the normal adult male range in the three treatmentgroups at baseline. None of the treatment groups showed major changesfrom these the baseline on any of the treatment visit days. Aftertestosterone replacement serum SHBG levels showed a small decrease inall three groups. The most marked change occurred in the 10.0 g/dayAndroGel® group. TABLE 14 SHBG Concentration (nmol/L) on Each of theObservation Days By Initial Treatment (Mean ± SD) Day 0 Day 30 Day 60Day 90 Day 120 Day 150 Day 180  5.0 g/day N = 73 N = 69 N = 69 N = 67 N= 66 N = 65 N = 65 T-gel 26.2 ± 14.9 24.9 ± 14.0 25.9 ± 14.4 25.5 ± 14.725.2 ± 14.1 24.9 ± 12.9 24.2 ± 13.6 10.0 g/day N = 78 N = 78 N = 75 N =75 N = 72 N = 68 N = 71 T-gel 26.6 ± 17.8 24.8 ± 14.5 25.2 ± 15.5 23.6 ±14.7 25.5 ± 16.5 23.8 ± 12.5 24.0 ± 14.5 T-Patch N = 76 N = 72 N = 68 N= 66 N = 50 N = 49 N = 49 30.2 ± 22.6 28.4 ± 21.3 28.2 ± 23.8 28.0 ±23.6 26.7 ± 16.0 26.7 ± 16.4 25.8 ± 15.1 Across RX 0.3565 0.3434 0.59330.3459 0.8578 0.5280 0.7668

h. Gonadotropins

[0155] Serum FSH and LH were measured by highly sensitive and specificsolid-phase FIA assays with reagents provided by Delfia (Wallac,Gaithersburg, Md.). The intra-assay coefficient of variations for LH andFSH fluroimmunometric assays were 4.3 and 5.2%, respectively; and theinterassay variations for LH and FSH were 11.0% and 12.0%, respectively.For both LH and FSH assays, the LLQ was determined to be 0.2 IU/L. Allsamples obtained from the same subject were measured in the same assay.The UCLA-Harbor Medical Center reports that the adult normal male rangefor LH is 1.0-8.1 U/L and for FSH is 1.0-6.9 U/L.

(1) FSH

[0156] Table 15(a)-(d) shows the concentrations of FSH throughout the180-day treatment depending on the cause of hypogonadism: (1) primary,(2) secondary, (3) age-associated, or (4) unknown.

[0157] As discussed above, patients with primary hypogonadism have anintact feedback inhibition pathway, but the testes do not secretetestosterone. As a result, increasing serum testosterone levels shouldlead to a decrease in the serum FSH concentrations. In this example, atotal of 94 patients were identified as having primary hypogonadism. Forthese patients, the mean FSH concentrations in the three treatmentgroups on day 0 were 21-26 mlU/mL, above the upper limit of the normalrange. As shown in FIG. 12(a) and Table 15(a), the mean FSHconcentrations decreased during treatment in all three treatmentregimens. However, only the 10.0 g/day AndroGel® group reduced the meanconcentrations to within the normal range during the first 90 days oftreatment. Treatment with the 10.0 g/day AndroGel® group requiredapproximately 120 days to reach steady state. The mean FSH concentrationin patients applying 5.0 g/day of AndroGel® showed an initial declinethat was completed by day 30 and another declining phase at day 120 andcontinuing until the end of treatment. Mean FSH concentrations in thepatients receiving the testosterone patch appeared to reached steadystate after 30 days but were significantly higher than the normal range.TABLE 15(a) FSH Concentrations (mlU/mL) on Each of the Observation Daysby Initial Treatment Group for Patients Having Primary Hypogonadism(Mean ± SD) N 5 g/day N 10 g/day N T-patch Day 0 26 21.6 ± 21.0 33 20.9± 15.9 34 25.5 ± 25.5 Day 30 23 10.6 ± 15.0 34 10.6 ± 14.1 31 21.4 ±24.6 Day 60 24 10.8 ± 16.9 32  7.2 ± 12.6 31 21.7 ± 23.4 Day 90 24 10.4± 19.7 31  5.7 ± 10.1 30 19.5 ± 20.0 Day 120 24  8.1 ± 15.2 28  4.6 ±10.2 21 25.3 ± 28.4 Day 150 22  6.7 ± 15.0 29  5.3 ± 11.0 21 18.6 ± 24.0Day 180 24  6.2 ± 11.3 28  5.3 ± 11.2 22 24.5 ± 27.4

[0158] Patients with secondary hypogonadism have a deficienttestosterone negative feedback system. As shown in FIG. 12(b), of 44patients identified as having secondary hypogonadism, the mean FSHconcentrations decreased during treatment, although the decrease overtime was not statistically significant for the testosterone patch. Thepatients in the 5.0 g/day AndroGel® group showed a decrease in the meanFSH concentration by about 35% by day 30, with no further decreaseevident by day 60. Beyond day 90, the mean FSH concentration in thepatients appeared to slowly return toward the pretreatment value. By day30, all of the 10.0 g/day AndroGel® group had FSH concentrations lessthan the lower limit. TABLE 15(b) FSH Concentrations (mlU/mL) on Each ofthe Observation Days by Initial Treatment Group for Patients HavingSecondary Hypogonadism (Mean ± SD) N 5 g/day N 10 g/day N T-patch Day 017 4.2 ± 6.6 12 2.1 ± 1.9 15 5.1 ± 9.0 Day 30 16 2.8 ± 5.9 12 0.2 ± 0.114 4.2 ± 8.0 Day 60 17 2.8 ± 6.1 12 0.2 ± 0.1 13 4.2 ± 7.4 Day 90 15 2.9± 5.6 12 0.2 ± 0.1 14 4.9 ± 9.0 Day 120 14 3.0 ± 6.1 12 0.1 ± 0.1 12 6.1 ± 10.7 Day 150 14 3.5 ± 7.5 12 0.2 ± 0.2 11 4.6 ± 6.5 Day 180 143.7 ± 8.6 12 0.1 ± 0.1 12 4.9 ± 7.4

[0159] Twenty-five patients were diagnosed with age-associatedhypogonadism. As shown in FIG. 12(c), the 5.0 g/day AndroGel® group hada mean pretreatment FSH concentration above the normal range. The meanconcentration for this group was within the normal range by day 30 andhad decreased more than 50% on days 90 and 180. The decrease in FSH meanconcentration in the 10.0 g/day AndroGel® group showed a more rapidresponse. The concentrations in all six patients decreased to below thelower normal limit by day 30 and remained there for the duration of thestudy. The six patients who received the testosterone patch exhibited noconsistent pattern in the mean FSH level; however, there was an overalltrend towards lower FHS levels with continued treatment. TABLE 15(c) FSHConcentrations (mlU/mL) on Each of the Observation Days by InitialTreatment Group for Patients Having Age-Related Hypogonadism (Mean ± SD)N 5 g/day N 10 g/day N T-patch Day 0 13 8.0 ± 9.1 6 5.2 ± 1.9 6 4.7 ± ±1.7 Day 30 12 4.6 ± 7.4 6 0.4 ± 0.3 6 3.7 ± 2.0 Day 60 12 3.9 ± 6.6 60.3 ± 0.3 4 4.3 ± 3.3 Day 90 11 3.8 ± 7.0 6 0.4 ± 0.7 4 3.5 ± 1.9 Day120 11 4.2 ± 8.3 6 0.4 ± 0.7 4 4.2 ± 3.3 Day 150 11 4.3 ± 8.1 5 0.2 ±0.2 4 3.4 ± 2.7 Day 180 11 4.0 ± 7.2 6 0.2 ± 0.2 4 2.7 ± 2.1

[0160] Sixty-four patients in the study suffered from unclassifiedhypogonadism. As shown in FIG. 12(d), the patients showed a marked andcomparatively rapid FSH concentration decrease in all three groups, withthe greatest decrease being in the 10.0 g/day AndroGel® group. The 10.0g/day AndroGel® group produced nearly a 90% decrease in the mean FSHconcentration by day 30 and maintained the effect to day 180. The 5.0g/day AndroGel® group produced about a 75% drop in mean FSHconcentration by day 30 and stayed at that level for the remainder oftreatment. The 21 patients receiving the testosterone patch had a 50%decrease in the mean FSH concentration by day 30, a trend that continuedto day 90 when the concentration was about one-third of its pretreatmentvalue. TABLE 15(d) Concentrations (mlU/mL) for FSH on Each of theObservation Days by Initial Treatment Group for Patients HavingUnknown-Related Hypogonadism (Mean ± SD) N 5 g/day N 10 g/day N T-patchDay 0 17 4.0 ± 1.8 26 4.1 ± 1.6 21 3.7 ± 1.4 Day 30 17 1.1 ± 1.0 26 0.5± 0.5 21 1.8 ± 0.8 Day 60 16 1.1 ± 1.1 26 0.3 ± 0.3 18 1.6 ± 1.0 Day 9017 1.1 ± 1.1 25 0.4 ± 0.7 18 1.2 ± 0.9 Day 120 16 1.2 ± 1.4 26 0.4 ± 0.612 1.4 ± 1.0 Day 150 17 1.4 ± 1.4 23 0.3 ± 0.5 13 1.4 ± 1.2 Day 180 161.0 ± 0.9 24 0.4 ± 0.4 11 1.3 ± 0.9

[0161] This data shows that feedback inhibition of FSH secretionfunctioned to some extent in all four subpopulations. The primaryhypogonadal population showed a dose-dependency in both the extent andrate of the decline in FSH levels. The sensitivity of the feedbackprocess appeared to be reduced in the secondary and age-associatedgroups in that only the highest testosterone doses had a significant andprolonged impact on FSH secretion. In contrast, the feedback inhibitionpathway in the patients in the unclassified group was quite responsiveat even the lowest dose of exogenous testosterone.

(2) LH

[0162] The response of LH to testosterone was also examined separatelyfor the same four subpopulations. Tables 16(a)-(d) shows the LHconcentrations throughout the treatment period.

[0163] As shown in FIG. 13(a) and Table 16(a), the LH concentrationsprior to treatment were about 175% of the upper limit of the normalrange in primary hypogonadal patients. The mean LH concentrationsdecreased during treatment in all groups. However, only the AndroGel®groups decreased the mean LH concentrations enough to fall within thenormal range. As with FSH, the primary hypogonadal men receivingAndroGel® showed dose-dependence in both the rate and extent of the LHresponse. TABLE 16(a) Concentrations for LH (mlU/mL) on Each of theObservation Days for Patients Having Primary Hypogonadism (Summary ofMean ± SD) N 5 g/day N 10 g/day N T-patch Day 0 26 12.2 ± 12.1 33 13.9 ±14.9 33 13.3 ± 14.3 Day 30 23 5.6 ± 7.6 34 5.9 ± 8.1 31 10.9 ± 12.9 Day60 24 6.8 ± 9.0 32  4.8 ± 10.0 31 10.8 ± 11.8 Day 90 24 5.9 ± 9.5 31 4.2 ± 11.0 30 10.0 ± 11.7 Day 120 24  6.4 ± 11.9 28  3.8 ± 10.4 21 11.5± 11.5 Day 150 22 4.4 ± 8.5 29  4.0 ± 11.3 21 7.4 ± 6.0 Day 180 24 4.8 ±6.8 28  4.0 ± 11.9 22 11.2 ± 10.5

[0164] The secondary hypogonadal men were less sensitive to exogenoustestosterone. For the 44 patients identified as having secondaryhypogonadism, the pretreatment mean concentrations were all within thelower limit normal range. The mean LH concentrations decreased duringtreatment with all three regimens as shown in FIG. 13(b) and Table16(b). TABLE 16(b) Concentrations for LH (mlU/mL) on Each of theObservation Days for Patients Having Secondary Hypogonadism (Summary ofMean ± SD) N 5 g/day N 10 g/day N T-patch Day 0 17 1.8 ± 2.6 12 1.4 ±1.8 15 1.6 ± 3.1 Day 30 16 1.1 ± 2.2 12 0.2 ± 0.2 14 0.4 ± 0.4 Day 60 171.4 ± 3.8 12 0.2 ± 0.2 13 0.6 ± 0.5 Day 90 15 1.2 ± 2.4 12 0.2 ± 0.2 140.7 ± 1.0 Day 120 14 1.6 ± 4.0 12 0.2 ± 0.2 12 0.8 ± 0.8 Day 150 14 1.6± 3.5 12 0.2 ± 0.2 11 1.2 ± 2.0 Day 180 14 1.5 ± 3.7 12 0.2 ± 0.2 12 1.4± 2.1

[0165] None of the 25 patients suffering from age-associatedhypogonadism had pretreatment LH concentrations outside of the normalrange as shown in FIG. 13(c) and Table 16(c). The overall time andtreatment effects were significant for the AndroGel® patients but notthose patients using the testosterone patch. TABLE 16(c) Concentrationsfor LH (mlU/mL) on Each of the Observation Days for Patients HavingAge-Related Hypogonadism (Summary of Mean ± SD) N 5 g/day N 10 g/day NT-patch Day 0 13 3.2 ± 1.1 6 2.4 ± 1.8 6 2.9 ± 0.6 Day 30 12 1.1 ± 1.0 60.1 ± 0.0 6 1.8 ± 1.1 Day 60 12 0.8 ± 0.7 6 0.2 ± 0.3 5 3.4 ± 2.8 Day 9011 0.9 ± 1.2 6 0.1 ± 0.0 4 2.3 ± 1.4 Day 120 11 1.0 ± 1.4 6 0.1 ± 0.0 42.2 ± 1.4 Day 150 11 1.3 ± 1.5 5 0.1 ± 0.0 4 1.9 ± 1.2 Day 180 11 1.8 ±2.1 6 0.1 ± 0.0 4 1.4 ± 1.0

[0166] Of the 64 patients suffering from an unclassified hypogonadism,none of the patients had a pretreatment LH concentration above the upperlimit. Fifteen percent, however, had pretreatment concentrations belowthe normal limit. The unclassified patients showed comparatively rapidLH concentration decreases in all treatment groups as shown in FIG.13(d) and Table 16(d). TABLE 16(d) Concentrations for LH (mlU/mL) onEach of the Observation Days for Patients Having Unknown-RelatedHypogonadism (Summary of Mean ± SD) N 5 g/day N 10 g/day N T-patch Day 017 1.8 ± 1.2 26 2.5 ± 1.5 21 2.5 ± 1.5 Day 30 17 0.3 ± 0.3 26 0.3 ± 0.321 1.3 ± 1.3 Day 60 17 0.4 ± 0.5 26 0.3 ± 0.3 18 1.2 ± 1.4 Day 90 17 0.5± 0.5 26 0.3 ± 0.4 18 1.0 ± 1.4 Day 120 17 0.4 ± 0.4 26 0.4 ± 0.5 12 1.2± 1.1 Day 150 17 0.8 ± 1.1 23 0.3 ± 0.4 13 1.1 ± 1.1 Day 180 15 0.3 ±0.4 25 0.4 ± 0.4 11 1.5 ± 1.3

(3) Summary LH and FSH

[0167] Patients receiving AndroGel® or the testosterone patch achieve“hormonal steady state” only after long-term treatment. Specifically,data involving FSH and LH show that these hormones do not achievesteady-state until many weeks after treatment. Because testosteroneconcentrations are negatively inhibited by FSH and LG, testosteronelevels do not achieve true steady state until these other hormones alsoachieve steady state. However, because these hormones regulate onlyendogenous testosterone (which is small to begin with in hypogonadalmen) in an intact feedback mechanism (which may not be present dependingon the cause of hypogonadism), the level of FSH and/or LH may havelittle effect on the actual testosterone levels achieved. The net resultis that the patients do not achieve a “hormonal steady state” fortestosterone even though the C_(avg), C_(min), and C_(max) fortestosterone remains relative constant after a few days of treatment.

2. Bone Mineral Density (“BMD”) and Similar Markers a. BMD

[0168] BMD was assessed by dual energy X-ray absorptiometry (“DEXA”)using Hologic QDR 2000 or 4500 A (Hologic, Waltham, Mass.) on days 0 and180 in the lumbar spine and left hip regions. BMD of spine wascalculated as the average of BMD at L1 to L4. BMD of the left hip, whichincluded Ward's triangle, was calculated by the average of BMD fromneck, trochanter, and intertrochanter regions. The scans were centrallyanalyzed and processed at Hologic. BMD assessments were performed at 13out of the 16 centers (206 out of 227 subjects) because of the lack ofthe specific DEXA equipment at certain sites.

[0169] Table 17 and FIGS. 14(a)-14(b) show that before treatment, theBMD of the hip or the spine was not different among the three treatmentgroups. Significant increases in BMD occurred only in subjects in theAndroGel® 10.0 g/day group and those who switched from AndroGel® 10.0 to7.5 g/day groups. The increases in BMD were about 1% in the hip and 2%in the spine during the six-month period. Average increases in BMD of0.6% and 1% in the hip and spine were seen in those receiving 5.0 g/dayof AndroGel® but no increase was observed in the testosterone patchgroup. TABLE 17 BMD Concentrations on Day 0 and Day 180 by FinalTreatment Group Mean (± SD) Final % Change from Treatment Group N Day 0N Day 180 N Day 0 to Day 180 Hip  5.0 g/day T-gel 50 1.026 ± 0.145 411.022 ± 0.145 41 0.7 ± 2.1  5.0 to 7.5 g/day T-gel 16 1.007 ± 0.233 151.011 ± 0.226 15 1.0 ± 4.9 10.0 to 7.5 g/day T-gel 20 1.002 ± 0.135 191.026 ± 0.131 19 1.3 ± 2.4 10.0 g/day T-gel 53 0.991 ± 0.115 44 0.995 ±0.130 44 1.1 ± 1.9 T-Patch 67 0.982 ± 0.166 37 0.992 ± 0.149 37 −0.2 ±2.9   Spine  5.0 g/day T-gel 50 1.066 ± 0.203 41 1.072 ± 0.212 41 1.0 ±2.9  5.0 to 7.5 g/day T-gel 16 1.060 ± 0.229 15 1.077 ± 0.217 15 0.4 ±5.5 10.0 to 7.5 g/day T-gel 19 1.049 ± 0.175 19 1.067 ± 0.175 18 1.4 ±3.2 10.0 g/day T-gel 53 1.037 ± 0.126 44 1.044 ± 0.124 44 2.2 ± 3.1T-Patch 67 1.058 ± 0.199 36 1.064 ± 0.205 36 −0.2 ± 3.4  

[0170] The baseline hip and spine BMD and the change in BMD on day 180were not significantly correlated with the average serum testosteroneconcentration on day 0. The changes in BMD in the hip or spine aftertestosterone replacement were not significantly different in subjectswith hypogonadism due to primary, secondary, aging, or unclassifiedcauses; nor were they different between naive and previouslytestosterone replaced subjects. The change in BMD in the spine wasnegatively correlated with baseline BMD values, indicating that thegreatest increase in BMD occurred in subjects with the lowest initialBMD. The increase in BMD in the hip (but not in the spine) aftertestosterone treatment was correlated with the change in serumtestosterone levels.

b. Bone Osteoblastic Activity Markers

[0171] The results described above are supported by measurements of anumber of serum and urine markers of bone formation. Specifically, themean concentrations of the serum markers (PTH, SALP, osteocalcin, type Iprocollagen) generally increase during treatment in all treatmentgroups. In addition, the ratios of two urine markers of bone formation(N-telopeptide/creatinine ratio and calcium/creatinine ratio) suggests adecrease in bone resorption.

(1) PTH (Parathyroid or Calciotropic Hormone)

[0172] Serum intact PTH was measured by two site immunoradiometric assay(“IRMA”) kits from Nichol's Institute (San Juan Capistrano, Calif.). TheLLC for the PTH assay was 12.5 ng/L. The intra- and inter-assaycoefficients of variation were 6.9 and 9.6%, respectively. TheUCLA-Harbor Medical Center has reported previously that the normal maleadult range of PTH is 6.8 to 66.4 ng/L.

[0173] Table 18 provides the PTH concentrations over the 180-day study.FIG. 15 shows that the mean serum PTH levels were within the normal malerange in all treatment groups at baseline. Statistically significantincreases in serum PTH were observed in all subjects as a group at day90 without inter-group differences. These increases in serum PTH weremaintained at day 180 in all three groups. TABLE 18 PTH Concentrationson Each of the Observation Days by Final Treatment Group (Mean ± SD) 5g/day 5 => 7.5 g/day 10 => 7.5 g/day 10 g/day N T-gel N T-gel N T-gel NT-gel N T-Patch Day 0 53 16.31 ± 8.81  20 17.70 ± 9.66  20 18.02 ± 8.18 58 14.99 ± 6.11  75 15.60 ± 6.57  Day 30 49 17.91 ± 10.36 20 18.33 ±8.02  20 17.45 ± 5.67  58 18.04 ± 8.95  72 18.33 ± 10.92 Day 90 47 21.32± 11.47 20 21.25 ± 10.96 19 17.10 ± 6.04  54 20.01 ± 9.77  66 21.45 ±13.71 Day 120 46 21.19 ± 11.42 19 21.42 ± 13.20 20 19.62 ± 9.96  5022.93 ± 12.57 46 21.07 ± 11.44 Day 180 46 22.85 ± 12.89 19 21.34 ± 11.0819 21.02 ± 10.66 51 25.57 ± 15.59 46 25.45 ± 16.54

(2) SALP

[0174] SALP was quantitated by IRMA using reagents supplied by Hybritech(San Diego, Calif.). The LLQ for the SALP assay was 3.8 μg/L.; and theintra- and inter-assay precision coefficients were 2.9 and 6.5%,respectively. The UCLA-Harbor Medical Center reported that the adultnormal male concentration of SALP ranges from 2.4 to 16.6 μg/L.

[0175] The pretreatment SALP concentrations were within the normalrange. FIG. 16 and Table 19 show that SALP levels increased withtestosterone treatment in the first 90 days and reached statisticaldifference in the testosterone patch group. Thereafter serum SALPplateaued in all treatment groups. TABLE 19 SALP Concentrations on Eachof the Observation Days by Final Treatment Group (Mean ± SD) 5 g/day 5=> g/day 10 => 7.5 10 g/day N T-gel N T-gel N g/day T-gel N T-gel NT-Patch Day 0 53  9.96 ± 5.61 20 12.36 ± 4.62 20 10.48 ± 3.68 58 9.80 ±3.57 76 10.44 ± 3.77 Day 30 49 10.20 ± 6.77 20 11.38 ± 4.09 20 11.83 ±4.32 58 9.93 ± 3.88 71 10.86 ± 3.75 Day 90 47 11.64 ± 7.98 20 11.97 ±5.03 20 10.97 ± 3.18 55 9.56 ± 3.12 65 11.99 ± 9.36 Day 120 46 11.71 ±7.85 19 12.12 ± 5.25 20 11.61 ± 2.58 48 9.63 ± 3.58 45 11.63 ± 4.72 Day180 45 11.12 ± 7.58 19 11.67 ± 5.35 19 11.22 ± 3.44 51 9.19 ± 2.42 4611.47 ± 3.77

(3) Osteocalcin

[0176] Serum osteocalcin was measured by an IRMA from Immutopics (SanClemente, Calif.). The LLQ was 0.45 μg/L. The intra- and inter- assaycoefficients were 5.6 and 4.4%, respectively. The UCLA-Harbor MedicalCenter reports that the normal male adult range for the osteocalcinassay ranges from 2.9 to 12.7 μg/L.

[0177] As shown in FIG. 17 and Table 20, the baseline mean serumosteocalcin levels were within the normal range in all treatment groups.During the first 90-day treatment, mean serum osteocalcin increased withtestosterone replacement in all subjects as a group without significantdifferences between the groups. With continued treatment serumosteocalcin either plateaued or showed a decrease by day 180. TABLE 20Osteocalcin Concentrations on Each of the Observation Days FinalTreatment Group (Mean ± SD) 5 g/day 5 => 7.5 g/day 10 => 7.5 g/day 10g/day N T-gel N T-gel N T-gel N T-gel N T-Patch Day 0 53 4.62 ± 1.55 205.01 ± 2.03 20 4.30 ± 1.28 58 4.58 ± 1.92 76 4.53 ± 1.54 Day 30 49 4.63± 1.65 20 5.35 ± 2.06 20 4.48 ± 1.72 58 4.91 ± 2.08 72 5.17 ± 1.61 Day90 47 4.91 ± 2.15 20 5.29 ± 1.87 19 4.76 ± 1.50 55 4.83 ± 2.13 66 5.18 ±1.53 Day 120 46 4.95 ± 1.97 18 4.97 ± 1.60 20 4.71 ± 1.39 49 4.61 ± 2.0147 4.98 ± 1.87 Day 180 45 4.79 ± 1.82 19 4.89 ± 1.54 19 4.47 ± 1.49 513.76 ± 1.60 46 5.15 ± 2.18

(4) Type I Procollagen

[0178] Serum type I procollagen was measured using a RIA kit fromIncstar Corp (Stillwater, Minn.). The LLQ of the procollagen assay was 5μg/L, and the intra- and inter-assay precisions were 6.6 and 3.6%,respectively. The UCLA-Harbor Medical Center reports that the normaladult male concentration of type I procollagen ranges from 56 to 310μg/L.

[0179]FIG. 18 and Table 21 show shat serum procollagen generallyfollowed the same pattern as serum osteocalcin. At baseline the meanlevels were similar and within the normal range in all treatment groups.With transdermal treatment, serum procollagen increased significantly inall subjects as a group without treatment group differences. Theincrease in procollagen was highest on day 30 and then plateaued untilday 120. By day 180, the serum procollagen levels returned to baselinelevels. TABLE 21 Procollagen Concentrations on Each of the ObservationDays by Final Treatment Group (Mean ± SD) 5 g/day 5 => 7.5 g/day 10 =>7.5 g/day 10 g/day N T-gel N T-gel N T-gel N T-gel N T-Patch Day 0 53115.94 ± 43.68 20 109.27 ± 32.70 20 120.93 ± 28.16 58 125.33 ± 57.57 76122.08 ± 51.74 Day 30 49 141.09 ± 64.02 20 141.41 ± 77.35 20 147.25 ±49.85 58 149.37 ± 60.61 71 139.26 ± 59.12 Day 90 47 137.68 ± 68.51 20129.02 ± 60.20 29 144.60 ± 58.20 55 135.59 ± 51.54 66 130.87 ± 49.91 Day120 46 140.07 ± 81.48 19 133.61 ± 54.09 20 139.00 ± 64.96 50 128.48 ±45.56 46 130.39 ± 42.22 Day 180 45 119.78 ± 49.02 19 108.78 ± 35.29 19123.51 ± 39.30 51 108.52 ± 38.98 45 120.74 ± 56.10

c. Urine Bone Turnover Markers N-telopeptide/Cr and Ca/Cr Ratios

[0180] Urine calcium and creatinine were estimated using standardclinical chemistry procedures by an autoanalyzer operated by theUCLA-Harbor Pathology Laboratory. The procedures were performed usingthe COBAS MIRA automated chemistry analyzer system manufactured by RocheDiagnostics Systems. The sensitivity of the assay for creatinine was 8.9mg/dL and the LLQ was 8.9 mg/dL. According to the UCLA-Harbor MedicalCenter, creatinine levels in normal adult men range from 2.1 mM to 45.1mM. The sensitivity of the assay for calcium was 0.7 mg/dL and the LLQwas 0.7 mg/dL. The normal range for urine calcium is 0.21 mM to 7.91 mM.

[0181] N-telopeptides were measured by an enzyme-linked immunosorbantassay (“ELISA”) from Ostex (Seattle, Wash.). The LLQ for theN-telopeptide assay was 5 nM bone collagen equivalent (“BCE”). Theintra- and inter-assay had a precision of 4.6 and 8.9%, respectively.The normal range for the N-telopeptide assay was 48-2529 nM BCE. Samplescontaining low or high serum/urine bone marker levels were reassayedafter adjusting sample volume or dilution to ensure all samples would beassayed within acceptable precision and accuracy.

[0182] The normal adult male range for the N-telopeptide/Cr ratio is 13to 119 nM BCE/nM Cr. As shown in FIG. 19 and Table 22, urinaryN-telopeptide/Cr ratios were similar in all three treatment groups atbaseline but decreased significantly in the AndroGel® 10.0 g/day groupbut not in the AndroGel® 5.0 g/day or testosterone patch group duringthe first 90 days of treatment. The decrease was maintained such thaturinary N-telopeptide/Cr ratio remained lower than baseline in AndroGel®10.0 g/day and in those subjects adjusted to 7.5 g/day from 10.0 g/daygroup at day 180. This ratio also decreased in the testosterone patchtreatment group by day 180. TABLE 22 N-Telopeptide/Cr Ratio on Each ofthe Observation Days by Initial Treatment Group (Mean ± SD) InitialTreatment 5.0 g.day 10.0 g/day Across-group Group N T-gel N T-gel NT-Patch p-value Day 0 71  90.3 ± 170.3 75  98.0 ± 128.2 75 78.5 ± 82.5 0.6986 Day 30 65 74.6 ± 79.3 73 58.4 ± 66.4 66 91.6 ± 183.6 0.3273 Day90 62 70.4 ± 92.6 73 55.2 ± 49.1 63 75.0 ± 113.5 0.5348 Day 120 35 78.8± 88.2 36 46.6 ± 36.4 21 71.2 ± 108.8 0.2866 Day 180 64 68.2 ± 81.1 7046.9 ± 43.1 47 49.4 ± 40.8  0.2285

[0183] The normal range for Ca/Cr ratio is 0.022 to 0.745 mM/mM. FIG. 20shows no significant difference in baseline urinary Ca/Cr ratios in thethree groups. With transdermal testosterone replacement therapy, urinaryCa/Cr ratios did not show a significant decrease in any treatment groupat day 90. With continued testosterone replacement to day 180, urinaryCa/Cr showed marked variation without significant changes in anytreatment groups. TABLE 23 Ca/Cr Ratio on Each of the Observation Daysby Initial Treatment Group (Mean ± SD) Initial Treatment 5.0 g.day 10.0g/day Across-group Group N T-gel N T-gel N T-Patch p-value Day 0 710.150 ± 0.113 75 0.174 ± 0.222 75 0.158 ± 0.137 0.6925 Day 30 65 0.153 ±0.182 73 0.128 ± 0.104 66 0.152 ± 0.098 0.3384 Day 90 63 0.136 ± 0.12273 0.113 ± 0.075 63 0.146 ± 0.099 0.2531 Day 120 36 0.108 ± 0.073 360.117 ± 0.090 21 0.220 ± 0.194 0.0518 Day 180 64 0.114 ± 0.088 70 0.144± 0.113 47 0.173 ± 0.108 0.0398

[0184] Interestingly, the change in Ca/Cr ratio from baseline at day 90was inversely related to the baseline Ca/Cr ratios. Similarly, thechange in urine N-telopeptide/Cr ratio was also inversely proportionalto the baseline N-telopeptide/Cr ratio (r=−0.80, p=0.0001). Thussubjects with the highest bone resorption markers at baseline showed thelargest decreases of these markers during transdermal testosteronereplacement. The decreases in urinary bone resorption markers were mostprominent in subjects who had highest baseline values, suggesting thathypogonadal subjects with the most severe metabolic bone diseaseresponded most to testosterone replacement therapy.

d. Serum Calcium

[0185] Serum calcium showed no significant inter-group differences atbaseline, nor significant changes after testosterone replacement. Serumcalcium levels showed insignificant changes during testosteronereplacement.

3. Libido, Sexual Performance, and Mood

[0186] Sexual function and mood were assessed by questionnaires thepatients answered daily for seven consecutive days before clinic visitson day 0 and on days 30, 60, 90, 120, 150, and 180 days during gel andpatch application. The subjects recorded whether they had sexual daydreams, anticipation of sex, flirting, sexual interaction (e.g., sexualmotivation parameters) and orgasm, erection, masturbation, ejaculation,intercourse (e.g., sexual performance parameters) on each of the sevendays. The value was recorded as 0 (none) or 1 (any) for analyses and thenumber of days the subjects noted a parameter was summed for theseven-day period. The average of the four sexual motivation parameterswas taken as the sexual motivation score and that of the five sexualmotivation parameters as the sexual motivation mean score (0 to 7). Thesubjects also assessed their level of sexual desire, sexual enjoyment,and satisfaction of erection using a seven-point Likert-type scale (0 to7) and the percent of fall erection from 0 to 100%. The subjects ratedtheir mood using a 0 to 7 score. The parameters assessed includedpositive mood responses: alert, friendly, full of energy, well/goodfeelings and negative mood responses: angry, irritable, sad, tired,nervous. Weekly average scores were calculated. The details of thisquestionnaire had been described previously and are fully incorporatedby reference. See Wang et al., Testosterone Replacement Therapy ImprovesMood in Hypogonadal Men—A Clinical Research Center Study, 81 J. CLINICALENDOCRINOLOGY & METABOLISM 3578-3583 (1996).

a. Libido

[0187] As shown in FIG. 21(a), at baseline, sexual motivation was thesame in all treatment groups. After transdermal testosterone treatment,overall sexual motivation showed significant improvement. The change inthe summary score from baseline, however, was not different among thethree treatment groups.

[0188] Libido was assessed from responses on a linear scale of: (1)overall sexual desire, (2) enjoyment of sexual activity without apartner, and (3) enjoyment of sexual activity with a partner. As shownin FIG. 21(b) and Table 24, as a group, overall sexual desire increasedafter transdermal testosterone treatment without inter-group difference.Sexual enjoyment with and without a partner (FIG. 21(c) and Tables 25and 26) also increased as a group.

[0189] Similarly the sexual performance score improved significantly inall subjects as a groups. The improvement in sexual performance frombaseline values was not different between transdermal preparations.TABLE 24 Overall Sexual Desire Changes From Day 0 to Day 180 by InitialTreatment Group (Mean ± SD) Change Initial From Within- Treatment Day 0to Group Group N Day 0 N Day 180 N Day 180 p-value  5.0 g/day 69 2.1 ±1.6 63 3.5 ± 1.6 60 1.4 ± 1.9 0.0001 T-gel 10.0 g/day 77 2.0 ±0 1.4 683.6 ± 1.6 67 1.5 ± 1.9 0.0001 T-gel T-Patch 72 2.0 ± 1.6 47 3.1 ± 1.9 451.6 ± 2.1 0.0001 Across- 0.8955 0.2247 0.8579 Groups p-value

[0190] TABLE 25 Level of Sexual Enjoyment Without a Partner Changes FromDay 0 to Day 180 by Initial Treatment Group (Mean ± SD) Change InitialFrom Within- Treatment Day 0 to Group Group N Day 0 N Day 180 N Day 180p-value  5.0 g/day 60 1.5 ± 1.9 51 1.9 ± 1.9 44 0.8 ± 1.4 0.0051 T-gel10.0 g/day 63 1.2 ± 1.4 53 2.2 ± 1.9 48 1.1 ± 1.6 0.0001 T-gel T-Patch66 1.4 ± 1.8 44 2.2 ± 2.3 40 1.0 ± 1.9 0.0026 Across- 0.6506 0.74610.6126 Groups p-value

[0191] TABLE 26 Level of Sexual Enjoyment With a Partner Change from Day0 to Day 180 by Initial Treatment Group (Mean ± SD) Change Initial FromWithin- Treatment Day 0 to Group Group N Day 0 N Day 180 N Day 180p-value  5.0 g/day 64 2.1 ± 2.1 55 2.6 ± 2.2 48 0.4 ± 2.2 0.0148 T-gel10.0 g/day 66 1.8 ± 1.7 58 3.0 ± 2.2 52 1.0 ± 2.3 0.0053 T-gel T-Patch61 1.5 ± 1.7 40 2.2 ± 2.4 35 0.7 ± 2.3 0.1170 Across- 0.2914 0.17380.3911 Groups p-value

b. Sexual Performance

[0192]FIG. 22(a) shows that while all treatment groups had the samebaseline sexual performance rating, the rating improved with transdermaltestosterone treatment in all groups. In addition, as a group, thesubjects' self-assessment of satisfaction of erection (FIG. 22(b) andTable 27) and percent full erection (FIG. 22(c) and Table 28) were alsoincreased with testosterone replacement without significant differencesbetween groups.

[0193] The improvement in sexual function was not related to the dose orthe delivery method of testosterone. Nor was the improvement related tothe serum testosterone levels achieved by the various testosteronepreparations. The data suggest that once a threshold (serum testosteronelevel probably at the low normal range) is achieved, normalization ofsexual function occurs. Increasing serum testosterone levels higher tothe upper normal range does not further improve sexual motivation orperformance. TABLE 27 Satisfaction with Duration of Erection Change fromDay 0 to Day 180 by Initial Treatment Group (Mean ± SD) Change InitialFrom Within- Treatment Day 0 to Group Group N Day 0 N Day 180 N Day 180p-value  5.0 g/day 55 2.5 ± 2.1 57 4.3 ± 1.8 44 1.9 ± 2.0 0.0001 T-gel10/0 g/day 64 2.9 ± 1.9 58 4.5 ± 1.7 53 1.5 ± 2.0 0.0001 T-gel T-Patch45 3.4 ± 2.1 34 4.5 ± 2.0 20 1.3 ± 2.1 0.0524 Across- 0.1117 0.70930.5090 Groups p-value

[0194] TABLE 28 Percentage of Full Erection Change from Day 0 to Day 180by Initial Treatment Group (Mean ± SD) Initial Treatment Change FromWithin-Group Group N Day 0 N Day 180 N Day 0 to Day 180 p-value  5.0g/day T-gel 53 53.1 ± 24.1 57 67.4 ± 22.5 43 18.7 ± 22.1 0.0001 10.0g/day T-gel 62 59.6 ± 22.1 59 72.0 ± 20.2 52 10.4 ± 23.4 0.0001 T-Patch47 56.5 ± 24.7 33 66.7 ± 26.7 19 12.7 ± 20.3 0.0064 Across-Groups 0.33600.4360 0.1947 p-value

c. Mood

[0195] The positive and negative mood summary responses to testosteronereplacement therapy are shown in FIGS. 23(a) and 23(b). All threetreatment groups had similar scores at baseline and all subjects as agroup showed improvement in positive mood. Similarly, the negative moodsummary scores were similar in the three groups at baseline and as agroup the responses to transdermal testosterone applications showedsignificant decreases without showing between group differences.Specifically, positive mood parameters, such as sense of well being andenergy level, improved and negative mood parameters, such as sadness andirritability, decreased. The improvement in mood was observed at day 30and was maintained with continued treatment. The improvement in moodparameters was not dependent on the magnitude of increase in the serumtestosterone levels. Once the serum testosterone increased into the lownormal range, maximal improvement in mood parameters occurred. Thus, theresponsiveness in sexual function and mood in hypogonadal men inresponse to testosterone therapy appeared to be dependent on reaching athreshold of serum testosterone at the low normal range.

4. Muscle Strength

[0196] Muscle strength was assessed on days 0, 90, and 180. Theone-repetitive maximum (“1-RM”) technique was used to measure musclemass in bench press and seated leg press exercises. The muscle groupstested included those in the hips, legs, shoulders, arms, and chest. The1-RM technique assesses the maximal force generating capacity of themuscles used to perform the test. After a 5-10 minute walking andstretching period, the test began with a weight believe likely torepresent the patient's maximum strength. The test was repeated usingincrements of about 2-10 pounds until the patient was unable to liftadditional weight with acceptable form Muscle strength was assessed in167 out of the 227 patients. Four out of 16 centers did not participatein the muscle strength testing because of lack of the requiredequipment.

[0197] The responses of muscle strength testing by the arm/chest and legpress tests are shown in FIG. 24(a) and 24(b) and Table 29. There wereno statistical significant differences in arm/chest or leg musclestrength among the three groups at baseline. In general, muscle strengthimproved in both the arms and legs in all three treatment groups withoutinter-group differences at both day 90 and 180. The results showed animprovement in muscle strength at 90 and 180 days, more in the legs thanthe arms, which was not different across treatment groups nor on thedifferent days of assessment. Adjustment of the dose at day 90 did notsignificantly affect the muscle strength responses to transdermaltestosterone preparations. TABLE 29 Muscle Strength - Days 0, 90, and180 Levels and Change (lbs.) from Day 0 to Day 90 and from Day 0 to Day180 by Final Treatment Group Final Arm/Chest (Bench Treatment StudySeated Leg Press Press) Group Day N Mean ± SD (lbs.) N Mean ± SD (lbs.) 5.0 g/day  0 37 356.8 ± 170.0 37 100.5 ± 37.4  T-gel  90 30 396.4 ±194.3 31 101.2 ± 30.7  □ 0-90 30 25.8 ± 49.2 31  4.0 ± 10.0 180 31 393.4± 196.6 31 99.7 ± 31.4 □ 0-180  31 19.9 ± 62.4 31  1.3 ± 13.0  7.5 g/day 0 16 302.8 ± 206.5 16 102.8 ± 48.9  T-gel  90 15 299.8 ± 193.9 15 109.5± 47.6  (from 5.0 □ 0-90 15 17.0 ± 88.4 15  5.0 ± 21.3 g/day) 180 14300.6 ± 203.0 14 108.5 ± 49.3  □ 0-180  14  −0.1 ± 110.2 14  5.6 ± 30.4 7.5 g/day  0 14 363.4 ± 173.8 14 123.3 ± 54.7  T-gel  90 14 401.6 ±176.6 14 134.6 ± 57.5  (From 10.0 □ 0-90 14 38.2 ± 42.9 14 11.3 ± 10.5g/day) 180 12 409.9 ± 180.2 14 132.3 ± 61.5  □ 0-180  12 33.9 ± 67.3 14 9.0 ± 18.7 10.0 g/day  0 45 345.9 ± 186.9 43 114.7 ± 55.1  T-gel  90 43373.5 ± 194.8 41 119.8 ± 54.2  □ 0-90 43 27.6 ± 45.1 41  4.6 ± 12.8 18036 364.4 ± 189.1 34 112.0 ± 45.5  □ 0-180  36 32.2 ± 72.3 34  1.9 ± 14.8T-Patch  0 55 310.4 ± 169.7 54 99.2 ± 43.1  90 46 344.9 ± 183.9 46 106.2± 44.0  □ 0-90 46 25.4 ± 37.0 46  3.2 ± 12.0 180 36 324.8 ± 199.0 35104.8 ± 44.8  □ 0-180  36 15.2 ± 54.7 35  2.3 ± 15.7

5. Body Composition

[0198] Body composition was measured by DEXA with Hologic 2000 or 4500Aseries on days 0, 90, and 180. These assessments were done in 168 out of227 subjects because the Hologic DEXA equipment was not available at 3out of 16 study centers. All body composition measurements werecentrally analyzed and processed by Hologic (Waltham, Mass.).

[0199] At baseline, there were no significant differences in total bodymass (“TBM”), total body lean mass (“TLN”), percent fat (“PFT”), andtotal body fat mass (“TFT”) in the three treatment groups. As shown inFIGS. 25(a) and Table 30, all treatment groups incurred an overallincrease in TBM. The increase in TBM was mainly due to the increases inTLN. FIG. 25(b) and Table 30 show that after 90 days of testosteronereplacement the increase in TLN was significantly higher in the 10.0g/day AndroGel® group than in the other two groups. At day 180, theincreases in TLN were further enhanced or maintained in all AndroGel®treated groups, as well as in the testosterone patch group.

[0200] FIGS. 25(c) and (d) show that the TFT and the PFT decreased inall transdermal AndroGel® treatment groups. At 90 days of treatment, TFTwas significantly reduced by in the 5.0 g/day and 10.0 g/day AndroGel®groups, but was not changed in the testosterone patch group. Thisdecrease was maintained at day 180. Correspondingly, at the 90 and 180,the decrease in PFT remained significantly lower in all AndroGel®treated groups but not significantly reduced in the testosterone patchgroup.

[0201] The increase in TLN and the decrease in TFT associated withtestosterone replacement therapy showed significant correlations withthe serum testosterone level attained by the testosterone patch and thedifferent doses of AndroGel®. Testosterone gel administered at 10.0g/day increased lean mass more than the testosterone patch and the 5.0g/day AndroGel® groups. The changes were apparent on day 90 aftertreatment and were maintained or enhanced at day 180. Such changes inbody composition was significant even though the subjects were withdrawnfrom prior testosterone therapy for six weeks. The decrease in TFT andPFT was also related to the serum testosterone achieved and weredifferent across the treatment groups. The testosterone patch group didnot show a decrease in PFT or TFT after 180 days of treatment. Treatmentwith AndroGel® (50 to 10.0 g/day) for 90 days reduced PFT and TFT. Thisdecrease was maintained in the 5.0 and 7.5 g/day groups at 180 days butwere further lowered with continued treatment with the higher dose ofthe AndroGel®. TABLE 30 Mean Change in Body Composition Parameters(DEXA) From Baseline to Day 90 and Baseline to Day 180 By FinalTreatment Groups Final Treatment Group N TFT (g) TLN (g) TBM (g) PFTMean Change from Day 0-Day 90  5.0 g/ 43  −782 ± 2105 1218 ± 2114  447 ±1971 −1.0 ± 2.2 day T-gel  7.5 g/ 12 −1342 ± 3212 1562 ± 3321  241 ±3545 −1.0 ± 3.1 day (from  5.0 g/ day)  7.5 g/ 16 −1183 ± 1323 3359 ±2425 2176 ± 2213 −2.0 ± 1.5 day (from 10.0 g/ day) 10.0 g/ 45  −999 ±1849 2517 ± 2042 1519 ± 2320 −1.7 ± 1.8 day T-gel T-Patch 52    11 ±1769 1205 ± 1913 1222 ± 2290 −0.4 ± 1.6 Mean Change from Day 0-Day 180 5.0 g/ 38  −972 ± 3191 1670 ± 2469  725 ± 2357 −1.3 ± 3.1 day T-gel 7.5 g/ 13 −1467 ± 3851 2761 ± 3513 1303 ± 3202 −1.5 ± 3.9 day (from 5.0 g/ day)  7.5 g/ 16 −1333 ± 1954 3503 ± 1726 2167 ± 1997 −2.2 ± 1.7day (from 10.0 g/ day) 10.0 g/ 42 −2293 ± 2509 3048 ± 2284  771 ± 3141−2.9 ± 2.1 day T-gel T-Patch 34  293 ± 2695  997 ± 2224 1294 ± 2764 −0.3± 2.2

6. Lipid Profile and Blood Chemistry

[0202] The serum total, HDL, and LDL cholesterol levels at baseline werenot significantly different in all treatment groups. With transdermaltestosterone replacement, there were no overall treatment effects norinter-group differences in serum concentrations of total, HDL- andLDL-cholesterol (FIG. 5(d)) and triglycerides (data not shown). Therewas a significant change of serum total cholesterol concentrations as agroup with time (p=0.0001), the concentrations on day 30, 90, and 180were significantly lower than day 0.

[0203] Approximately 70 to 95% of the subjects had no significant changein their serum lipid profile during testosterone replacement therapy.Total cholesterol levels which were initially high were lowered into thenormal range (of each center's laboratory) at day 180 in 17.2, 20.4, and12.2% of subjects on testosterone patch, AndroGel® 5.0 g/day andAndroGel® 10.0 g/day, respectively. Serum HDL-cholesterol levels(initially normal) were reduced to below the normal range (of eachcenter's laboratory) in 9.8, 4.0, 9.1, and 12.5% of subjects at day 180in the testosterone patch, AndroGel® 5.0, 7.5, and 10.0 g/day groups,respectively. There was no clinically significant changes in renal orliver function tests in any treatment group.

7. Skin Irritations

[0204] Skin irritation assessments were performed at every clinic visitusing the following scale: 0=no erythema; 1=minimal erythema; 2=moderateerythema with sharply defined borders; 3=intense erythema edema; and4=intense erythema with edema and blistering/erosion.

[0205] Tolerability of the daily application of AndroGel® at the testeddosages was much better than with the permeation-enhanced testosteronepatch. Minimal skin irritation (erythema) at the application site wasnoted in three patients in the AndroGel® 5.0 g/day group (5.7%) andanother three in the AndroGel® 10.0 g/day group (5.3%). Skin irritationvarying in intensity from minimal to severe (mild erythema to intenseedema with blisters) occurred in 65.8% of patients in the patch group.Because of the skin irritation with the testosterone patch, 16 subjectsdiscontinued the study; 14 of these had moderate to severe skinreactions at the medication sites. No patients who received AndroGel®discontinued the study because of adverse skin reactions. The opensystem and the lower concentration of alcohol in the AndroGel®formulation markedly reduced skin irritation resulting in bettertolerability and continuation rate on testosterone replacement therapy.

[0206] Moreover, based on the difference in the weight of the dispensedand returned AndroGel® bottles, the mean compliance was 93.1% and 96.0%for the 5.0 g/day and 10.0 g/day AndroGel® groups during days 1-90,respectively. Compliance remained at over 93% for the three AndroGel®groups from days 91-180. In contrast, based on counting the patchesreturned by the subjects, the testosterone patch compliance was 65%during days 1-90 and 74% during days 91-180. The lower compliance in thetestosterone patch group was mostly due to skin reactions from thesubjects' records. TABLE 31 Incidence of Skin-Associated Adverse Events:Day 1 to Day 180 in Patients Who Remained on Initial Treatment 5.0 g/day10.0 g/day T-gel T-gel T-Patch N = 53 N = 57 N = 73 Total 16 (30.2%) 18(31.6%) 50 (68.5%) Application Site Reaction 3 (5.7%) 3 (5.3%) 48(65.8%) Acne 1 (1.9%) 7 (12.3%) 3 (4.1%) Rash 4 (7.5%) 4 (7.0%) 2 (2.7%)Skin Disorder 2 (3.8%) 1 (1.8%) 1 (1.4%) Skin Dry 2 (3.8) 0 (0.0%) 1(1.4%) Sweat 0 (0.0%) 2 (3.5%) 0 (0.0%) Reaction Unevaluable 2 (3.6%) 1(1.7%) 0 (0.0%) Cyst 0 (0.0%) 0 (0.0%) 2 (2.7%)

Example 2 Gel Delivery Dosage Forms and Devices

[0207] The present invention is also directed to a method for dispensingand packaging the gel. In one embodiment, the invention comprises ahand-held pump capable of delivering about 2.5 g of testosterone gelwith each actuation. In another embodiment, the gel is packaged in foilpackets comprising a polyethylene liner. Each packet holds about 2.5 gof testosterone gel. The patient simply tears the packet along aperforated edge to remove the gel. However, because isopropyl myristatebinds to the polyethylene liner, additional isopropyl myristate is addedto the gel in order to obtain a pharmaceutically effective gel whenusing this delivery embodiment. Specifically, when dispensing the gelvia the foil packet, about 41% more isopropyl myristate is used in thegel composition (i.e., about 0.705 g instead of about 0.5 g in Table 5),to compensate for this phenomenon.

[0208] The composition can also be dispensed from a rigid multi-dosecontainer (e.g., with a hand pump) having a larger foil packet of thecomposition inside the container. Such larger packets also comprise apolyethylene liner as above.

[0209] Both embodiments permit a patient to deliver accurate butincremental amounts of gel (e.g., either 2.5 g, 5.0 g, 7.5 g, etc.) tothe body. These delivery mechanisms thus permit the gel to beadministered in unit dose form depending on the particular needs andcharacteristics of the patient.

[0210] Although the invention has been described with respect tospecific embodiments and examples, it should be appreciated that otherembodiments utilizing the concept of the present invention are possiblewithout departing from the scope of the invention. Th present inventionis defined by the claimed elements, and any and all modifications,variations, or equivalents that fall within the true spirit and scope ofthe underlying principles.

We claim:
 1. A method of treating hypogonadism in a male subject,comprising: applying a hydroalcoholic gel containing testosterone toskin of the male subject in an amount effective to treat thehypogonadism.
 2. The method of claim 1, wherein the application is for aperiod of at least 7 days.
 3. The method of claim 1, wherein the periodis at least 30 days.
 4. The method of claim 1, wherein the period is atleast 180 days.
 5. The method of claim 1, wherein the application of thehydroalcoholic gel exhibits dose proportionality.
 6. The method of claim1, wherein the application results in a steady-state testosterone24-hour pharmacokinetic profile in the male subject, having a smallincrease at about two hours after application followed by a decrease toa testosterone concentration that remains relatively constant for theremainder of the day.
 7. The method of claim 6, wherein the applicationresults in a steady-state testosterone 24-hour pharmacokinetic profileapproximating the profile shown in FIG. 1(c).
 8. The method of claim 6,wherein the relatively constant testosterone serum concentration isbetween about 300 ng/dL and about 1,000 ng/dL.
 9. The method of claim 1,wherein the application causes an increased average dihydrotestosteroneserum concentration in the male subject.
 10. The method of claim 1,wherein the application causes an increase in the bone mineral densityof the male subject.
 11. The method of claim 10, wherein the increase inthe bone mineral density occurs in the spine and/or hip.
 12. The methodof claim 1, wherein the application causes increased libido in the malesubject.
 13. The method of claim 1, wherein the application causesimproved sexual performance in the male subject.
 14. The method of claim13, wherein the improved sexual performance comprises an increase in thepercentage of full erection by the male subject.
 15. The method of claim1, wherein the application causes improved mood in the male subject. 16.The method of claim 1, wherein the application causes increased musclestrength in the male subject.
 17. The method of claim 16, wherein theincreased muscle strength occurs in the legs of the male subject. 18.The method of claim 1, wherein the application causes improved bodycomposition in the male subject.
 19. The method in claim 18, wherein theimproved body composition comprises a decrease in the fat percentage ofthe male subject.
 20. The method of claim 1, wherein the applicationcauses negligible skin irritation.
 21. The method of claim 1, whereinthe testosterone C_(max) and C_(min) is within the normal range of aneugonadal male subject.
 22. A method of treating hypogonadism in a malesubject, comprising: applying a hydroalcoholic gel to skin of the malesubject in an amount effective to treat the hypogonadism, wherein thehydroalcoholic gel comprises testosterone, and a penetration enhancerselected from the group consisting of isostearic acid, octanoic acid,lauryl alcohol, ethyl oleate, isopropyl myristate, butyl stearate,methyl laurate, diisopropyl adipate, glyceryl monolaurate,tetrahydrofurfuryl alcohol, polyethylene glycol ether, polyethyleneglycol, propylene glycol, 2-(2-ethoxyethoxy) ethanol, diethylene glycolmonomethyl ether, alkylaryl ethers of polyethylene oxide, polyethyleneoxide monomethyl ethers, polyethylene oxide dimethyl ethers, dimethylsulfoxide, glycerol, ethyl acetate, acetoacetic ester,N-alkylpyrrolidone, and terpene, and mixtures thereof.
 23. The method ofclaim 22, wherein the hydroalcoholic gel further comprises a C1-C4alcohol comprising at least one of ethanol, 2-propanol, n-propanol, andmixtures thereof.
 24. The method of claim 22, wherein the testosteroneis present in a concentration of about 0.1% to about 10% weight toweight of the hydroalcoholic gel.
 25. The method of claim 22, whereinthe testosterone is present in a concentration of about 0.5% to about 5%weight to weight of the hydroalcoholic gel.
 26. The method of claim 22,wherein the testosterone is present in a concentration of about 1%weight to weight of the hydroalcoholic gel.
 27. The method of claim 22,wherein the testosterone comprises an enantiomer, a racemic mixture, aderivative, or a base or salt thereof.
 28. The method of claim 22,wherein the penetration enhancer is isopropyl myristate.
 29. The methodof claim 28, wherein the isopropyl myristate is present in aconcentration of about 0.1% to about 5% weight to weight of thehydroalcoholic gel.
 30. The method of claim 28, wherein the isopropylmyristate is present in a concentration of about 0.5% weight to weightof the hydroalcoholic gel.
 31. The method of claim 22, wherein thepenetration enhancer is lauryl alcohol.
 32. The method of claim 22,wherein the hydroalcoholic gel further comprises polyacrylic acid. 33.The method of claim 32, wherein the polyacrylic acid is present in aconcentration of about 0.1% to about 5% weight to weight of thehydroalcoholic gel.
 34. The method of claim 22, wherein thehydroalcoholic gel further comprises sodium hydroxide.
 35. A method oftreating hypogonadism in a male subject, comprising: applying ahydroalcoholic gel to skin of the male subject in an amount effective totreat the hypogonadism, wherein the hydroalcoholic gel comprisestestosterone, a C1-C4 alcohol, and a penetration enhancer selected fromthe group consisting of isopropyl myristate and lauryl alcohol.
 36. Themethod of claim 35, wherein the alcohol is ethanol.
 37. The method ofclaim 35, wherein the penetration enhancer is isopropyl myristate. 38.The method of claim 35, wherein the penetration enhancer is laurylalcohol.
 39. The method of claim 38, wherein the isopropyl myristate ispresent in a concentration of about 0.1% to about 5% weight to weight ofthe hydroalcoholic gel.
 40. The method of claim 35, wherein theisopropyl myristate is present in a concentration of about 0.5% weightto weight of the hydroalcoholic gel.
 41. The method of claim 35, whereinthe lauryl alcohol is present in an amount of about 0.1% to about 3%weight to weight of the hydroalcoholic gel.
 42. The method of claim 35,wherein the hydroalcoholic gel further comprises polyacrylic acid. 43.The method of claim 42, wherein the polyacrylic acid is present in aconcentration of about 0.1% to about 5% weight to weight of thehydroalcoholic gel.
 44. The method of claim 35, wherein the testosteroneis present in a concentration of about 0.1% to about 10% weight toweight of the hydroalcoholic gel.
 45. The method of claim 35, whereinthe testosterone is present in a concentration of about 0.5% to about 5%weight to weight of the hydroalcoholic gel.
 46. The method of claim 35,wherein the testosterone is present in a concentration of about 1%weight to weight of the hydroalcoholic gel.
 47. The method of claim 35,wherein the testosterone comprises an enantiomer, a racemic mixture, aderivative, or a base or salt thereof.
 48. A method of treatinghypogonadism in a male subject, comprising: applying a hydroalcoholicgel to skin of the male subject in an amount effective to treat thehypogonadism, wherein the hydroalcoholic gel comprises about 0.5% toabout 5% testosterone, about 0.1% to about 2% polyacrylic acid, about0.1% to about 2% isopropyl myristate, and about 40% to about 90%ethanol, wherein such percentages are weight to weight of thehydroalcoholic gel.
 49. The method of claim 48, wherein the testosteroneis present in a concentration of about 1%, the ethanol is present in aconcentration of about 72.5%, the isopropyl myristate is present in aconcentration of about 0.5%, and the polyacrylic acid is present in aconcentration of about 0.9% wherein such percentages are weight toweight of the hydroalcoholic gel.
 50. The method of claim 49, whereinthe hydroalcoholic gel further comprising water.
 51. The method of claim49, wherein the hydroalcoholic gel further comprises sodium hydroxide.52. A method of treating hypogonadism in a male subject, comprising:applying a hydroalcoholic gel to skin of the male subject in an amounteffective to treat the hypogonadism, wherein the hydroalcoholic gelcomprises testosterone, a C1-C4 alcohol, and isopropyl myristate. 53.The method of claim 52, wherein the gel weighs about 1.0 grams to 10.0grams.
 54. The method of claim 52, wherein the gel weighs about 2.5grams to about 7.5 grams.
 55. The method of claim 52, wherein the gelweighs about 2.5 grams to about 5.0 grams.
 56. The method of claim 52,wherein the testosterone is present in a concentration of about 0.1% toabout 10% weight to weight of the hydroalcoholic gel.
 57. The method ofclaim 52, wherein the testosterone is present in a concentration ofabout 0.5% to about 5% weight to weight of the hydroalcoholic gel. 58.The method of claim 52, wherein the testosterone is present in aconcentration of about 1% weight to weight of the hydroalcoholic gel.59. The method of claim 52, wherein the testosterone comprises anenantiomer, a racemic mixture, a derivative, or a base or salt thereof.60. The method of claim 52, wherein the isopropyl myristate is presentin a concentration of about 0.1% to about 5% weight to weight of thehydroalcoholic gel.
 61. The method of claim 52, wherein the isopropylmyristate is present in a concentration of about 0.5% weight to weightof the hydroalcoholic gel.
 62. The method of claim 52, wherein thehydroalcoholic gel further comprising polyacrylic acid.
 63. The methodof claim 62, wherein the polyacrylic acid is present in a concentrationof about 0.1% to about 5% weight to weight of the hydroalcoholic gel.64. The method of claim 52, wherein the alcohol is about 40% to about90% ethanol weight to weight of the hydroalcoholic gel.
 65. A method oftreating hypogonadism in a male subject, comprising: applying ahydroalcoholic gel to skin of the male subject in an amount effective totreat the hypogonadism, wherein the hydroalcoholic gel is in a unit dosepacket comprising a foil container having an inner surface and an outersurface, and a pharmaceutical composition inside the container, thecomposition comprising testosterone, a C1-C4 alcohol, and isopropylmyristate.
 66. The method of claim 65, wherein the composition weighsabout 1.0 grams to about 10.0 grams.
 67. The method of claim 65, whereinthe composition weighs about 2.5 grams to about 5.0 grams.
 68. Themethod of claim 65, wherein the composition is a hydroalcoholic gel. 69.The method of claim 68, wherein the gel weighs about 2.5 grams to about10.0 grams.
 70. The method of claim 65, wherein the testosterone ispresent in a concentration of about 0.1% to about 10% weight to weightof the composition.
 71. The method of claim 65, wherein the testosteroneis present in a concentration of about 0.5% to about 5% weight to weightof the composition.
 72. The method of claim 65, wherein the testosteroneis present in a concentration of about 1% weight to weight of thecomposition.
 73. The method of claim 65, wherein the testosteronecomprises an enantiomer, a racemic mixture, a derivative, or a base orsalt thereof.
 74. The method of claim 65, wherein the isopropylmyristate is present in a concentration of about 0.1% to about 5% weightto weight of the composition.
 75. The method of claim 65, wherein theisopropyl myristate is present in a concentration of about 0.5% to about0.7% weight to weight of the composition.
 76. The method of claim 65,further comprising polyacrylic acid.
 77. The method of claim 76, whereinthe polyacrylic acid is present in a concentration of about 0.1% toabout 5% weight to weight of the composition.
 78. The method of claim77, wherein the alcohol is about 40% to about 90% ethanol weight toweight of the composition.
 79. The method of claim 78, wherein thepacket further comprises a polyethylene liner between the inner surfaceand the composition.